Triazole compounds and methods of making and using the same

ABSTRACT

The present invention provides triazole macrocyclic compounds useful as therapeutic agents. More particularly, these compounds are useful as anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents. These compounds are represented by the following formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , etc. are defined as in claim  1.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/918,344, now allowed, filed Jun. 14, 2013, which is a continuationapplication of U.S. patent application Ser. No. 11/990,833, filed Sep.16, 2009, now U.S. Pat. No. 8,470,985, which is a national stageapplication, filed under 35 U.S.C. §371, of International ApplicationNo. PCT/US2006/033157, filed Aug. 24, 2006, which claims the benefit ofand priority to U.S. Patent Application No. 60/711,440, filed Aug. 24,2005, and U.S. Patent Application No. 60/797,926, filed May 5, 2006, allof which are incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates generally to the field of anti-infective,anti-proliferative, anti-inflammatory, and prokinetic agents. Moreparticularly, the invention relates to a family of triazole macrocycliccompounds that are useful as such agents.

BACKGROUND

Since the discovery of penicillin in the 1920s and streptomycin in the1940s, many new compounds have been discovered or specifically designedfor use as antibiotic agents. It was once believed that infectiousdiseases could be completely controlled or eradicated with the use ofsuch therapeutic agents. However, such beliefs have been shaken becausestrains of cells or microorganisms resistant to currently effectivetherapeutic agents continue to evolve. In fact, virtually everyantibiotic agent developed for clinical use has ultimately encounteredproblems with the emergence of resistant bacteria. For example,resistant strains of Gram-positive bacteria such asmethicillin-resistant staphylococci, penicillin-resistant streptococci,and vancomycin-resistant enterococci have developed. These resistantbacteria can cause serious and even fatal results for patients infectedwith such resistant bacteria. Bacteria that are resistant to macrolideantibiotics have emerged. Also, resistant strains of Gram-negativebacteria such as H. influenzae and M. catarrhalis have been identified.See, e.g., F. D. Lowry, “Antimicrobial Resistance: The Example ofStaphylococcus aureus.” J. Clin. Invest., vol. 111, no. 9, pp. 1265-1273(2003); and Gold, H. S. and Moellering, R. C., Jr., “Antimicrobial-DrugResistance,” N. Engl. J. Med., vol. 335, pp. 1445-53 (1996).

The problem of resistance is not limited to the area of anti-infectiveagents. Resistance has also been encountered with anti-proliferativeagents used in cancer chemotherapy. Therefore, the need exists for newanti-infective and anti-proliferative agents that are both effectiveagainst resistant bacteria and resistant strains of cancer cells.

Despite the problem of increasing antibiotic resistance, no new majorclasses of antibiotics have been developed for clinical use since theapproval in the United States in 2000 of the oxazolidinonering-containing antibiotic, linezolid, which is sold under the tradename Zyvox®. See, R. C. Moellering, Jr., “Linezolid: The FirstOxazolidinone Antimicrobial,” Annals of Internal Medicine, vol. 138, no.2, pp. 135-142 (2003). Linezolid was approved for use as ananti-bacterial agent active against Gram-positive organisms. However,linezolid-resistant strains of organisms are already being reported.See, Tsiodras et al., Lancet, vol. 358, p. 207 (2001); Gonzales et al.,Lancet, vol 357, p. 1179 (2001); Zurenko et al., Proceedings Of The39^(th) Annual Interscience Conference On Antibacterial Agents AndChemotherapy (ICAAC), San Francisco, Calif., USA (Sep. 26-29, 1999).

Another class of antibiotics is the macrolides, so named for theircharacteristic 14- to 16-membered ring. The macrolides also often haveone or more 6-membered sugar-derived rings attached to the mainmacrolide ring. The first macrolide antibiotic to be developed waserythromycin, which was isolated from a soil sample from the Philippinesin 1952. Even though erythromycin has been one of the most widelyprescribed antibiotics, its disadvantages are relatively lowbioavailability, gastrointestinal side effects, and a limited spectrumof activity. Another macrolide is the compound, azithromycin, which isan azolide derivative of erythromycin incorporating a methyl-substitutednitrogen in the macrolide ring. Azithromycin is sold under the tradename Zithromax®. A more recently introduced macrolide is telithromycin,which is sold under the trade name Ketek®. Telithromycin is asemisynthetic macrolide in which a hydroxyl group of the macrolide ringhas been oxidized to a ketone group. See Yong-Ji Wu, Highlights ofSemi-synthetic Developments from Erythromycin A, Current Pharm. Design,vol. 6, pp. 181-223 (2000), and Yong-Ji Wu and Wei-uo Su, RecentDevelopments on Ketolides and Macrolides, Curr. Med. Chem., vol. 8, no.14, pp. 1727-1758 (2001).

In the search for new therapeutic agents, researchers have triedcombining or linking various portions of antibiotic molecules to createmultifunctional or hybrid compounds. Other researches have tried makingmacrolide derivatives by adding further substituents to the largemacrolide ring or associated sugar rings. However, this approach formaking macrolide derivatives has also met with limited success.

Notwithstanding the foregoing, there is an ongoing need for newanti-infective and anti-proliferative agents. Furthermore, because manyanti-infective and anti-proliferative agents have utility asanti-inflammatory agents and prokinetic agents, there is also an ongoingneed for new compounds useful as anti-inflammatory and prokineticagents. The present invention provides compounds that meet these needs.

SUMMARY OF THE INVENTION

The invention provides compounds useful as anti-infective agents and/oranti-proliferative agents, for example, anti-biotic agents,anti-microbial agents, anti-bacterial agents, anti-fungal agents,anti-parasitic agents, anti-viral agents, and chemotherapeutic agents.The present invention also provides compounds useful asanti-inflammatory agents, and/or prokinetic (gastrointestinalmodulatory) agents. The present invention also provides pharmaceuticallyacceptable salts, esters, N-oxides, or prodrugs thereof.

The present invention provides compounds having the structure:

or a stereoisomer, pharmaceutically acceptable salt, ester, N-oxide, orprodrug thereof. In the formula, variables A, G, T, R¹, R², and R³ canbe selected from the respective groups of chemical moieties laterdefined in the detailed description. In addition, the invention providesmethods of synthesizing the foregoing compounds. Following synthesis, atherapeutically effective amount of one or more of the compounds can beformulated with a pharmaceutically acceptable carrier for administrationto a mammal, particularly humans, for use as an anti-cancer,anti-biotic, anti-microbial, anti-bacterial, anti-fungal, anti-parasiticor anti-viral agent, or to treat a proliferative disease, aninflammatory disease or a gastrointestinal motility disorder, or tosuppress disease states or conditions caused or mediated by nonsense ormissense mutations. Accordingly, the compounds or the formulations canbe administered, for example, via oral, parenteral, or topical routes,to provide an effective amount of the compound to the mammal.

The foregoing and other aspects and embodiments of the invention can bemore fully understood by reference to the following detailed descriptionand claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a family of compounds that can be used asanti-proliferative agents and/or anti-infective agents. The compoundscan be used without limitation, for example, as anti-cancer,anti-microbial, anti-bacterial, anti-fungal, anti-parasitic and/oranti-viral agents. Further, the present invention provides a family ofcompounds that can be used without limitation as anti-inflammatoryagents, for example, for use in treating chronic inflammatory airwaydiseases, and/or as prokinetic agents, for example, for use in treatinggastrointestinal motility disorders such as gastroesophageal refluxdisease, gastroparesis (diabetic and post surgical), irritable bowelsyndrome, and constipation. Further, the compounds can be used to treator prevent a disease state in a mammal caused or mediated by a nonsenseor missense mutation.

The compounds described herein can have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom canbe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and can be isolated as a mixture of isomers or as separateisomeric forms. All chiral, diastereomeric, racemic, and geometricisomeric forms of a structure are intended, unless specificstereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention. All tautomers of shown or described compounds are alsoconsidered to be part of the present invention.

1. DEFINITIONS

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R³) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with one or more R³moieties, then the group can optionally be substituted with one, two,three, four, five, or more R³ moieties, and R³ at each occurrence isselected independently from the definition of R³. Also, combinations ofsubstituents and/or variables are permissible, but only if suchcombinations result in stable compounds.

A chemical structure showing a dotted line representation for a chemicalbond indicates that the bond is optionally present. For example, adotted line drawn next to a solid single bond indicates that the bondcan be either a single bond or a double bond.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent can be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent can be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

In cases wherein there are nitrogens in the compounds of the presentinvention, these can be converted to N-oxides by treatment with anoxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford othercompounds of the present invention. Thus, all shown and claimednitrogens are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

As used herein, the term “anomeric carbon” means the acetal carbon of aglycoside.

As used herein, the term “glycoside” is a cyclic acetal.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. C₁₋₆ alkyl is intended to include C₁,C₂, C₃, C₄, C₅, and C₆ alkyl groups. C₁₋₈ alkyl is intended to includeC₁, C₂, C₃, C₄, C₅, C₆, C₇, and C₈ alkyl groups. Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, i-propyl,n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, andn-octyl.

As used herein, “alkenyl” Is intended to include hydrocarbon chains ofeither straight or branched configuration and one or more unsaturatedcarbon-carbon bonds that can occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₆ alkenyl is intended to include C₂,C₃, C₄, C₅, and C₆ alkenyl groups. C₂₋₆ alkenyl is intended to includeC₂, C₃, C₄, C₅, C₆, C₇, and C₈ alkenyl groups.

As used herein, “alkynyl” is intended to include hydrocarbon chains ofeither straight or branched configuration and one or more triplecarbon-carbon bonds that can occur in any stable point along the chain,such as ethynyl and propynyl. C₂₋₆ alkynyl is intended to include C₂,C₃, C₄, C₅, and C₆ alkynyl groups. C₂₋₈ alkynyl is intended to includeC₂, C₃, C₄, C₅, C₆, C₇, and C₈ alkynyl groups.

Furthermore, “alkyl”, “alkenyl”, and “alkynyl” are intended to includemoieties which are diradicals, i.e., having two points of attachment, anexample of which in the present invention is when D is selected fromthese chemical groups. A nonlimiting example of such an alkyl moietythat is a diradical is —CH₂CH₂—, i.e., a C₂ alkyl group that iscovalently bonded via each terminal carbon atom to the remainder of themolecule.

As used herein, the terms used to describe various carbon-containingmoieties, including, for example, “alkyl,” “alkenyl,” “alkynyl,”“phenyl,” and any variations thereof, are intended to include univalent,bivalent, or multivalent species. For example, “C₁₋₆ alkyl-R³” isintended to represent a univalent C₁₋₆ alkyl group substituted with a R³group, and “O—C₁₋₆ alkyl-R³” is intended to represent a bivalent C₁₋₆alkyl group, i.e., an “alkylene” group, substituted with an oxygen atomand a R³ group.

As used herein, “cycloalkyl” is intended to include saturated ringgroups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C₃₋₈ cycloalkylis intended to include C₃, C₄, C₅, C₆, C₇, and C₈ cycloalkyl groups.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo. “Counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl.

As used herein, “alkoxy” refers to an alkyl group as defined above withthe indicated number of carbon atoms attached through an oxygen bridge.C₁₋₆ alkoxy, is intended to include C₁, C₂, C₃, C₄, C₃, and C₆ alkoxygroups. C₁₋₆ alkoxy, is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇,and C₈ alkoxy groups. Examples of alkoxy include, but are not limitedto, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy,n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy.

As used herein, “alkylthio” refers to an alkyl group as defined abovewith the indicated number of carbon atoms attached through an sulfurbridge. C₁₋₆ alkylthio, is intended to include C₁, C₂, C₃, C₄, C₅, andC₆ alkylthio groups. C₁₋₈ alkylthio, is intended to include C₁, C₂, C₃,C₄, C₅, C₆, C₇, and C₈ alkylthio groups.

As used herein, “carbocycle” or “carbocyclic ring” is intended to mean,unless otherwise specified, any stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or12-membered monocyclic, bicyclic or tricyclic ring, any of which can besaturated, unsaturated (including partially and fully unsaturated), oraromatic, recognizing that rings with certain numbers of members cannotbe bicyclic or tricyclic. e.g., a 3-membered ring can only be amonocyclic ring. Examples of such carbocycles include, but are notlimited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane,[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,and tetrahydronaphthyl. As shown above, bridged rings are also includedin the definition of carbocycle (e.g., [2.2.2]bicyclooctane). A bridgedring occurs when one or more carbon atoms link two non-adjacent carbonatoms. Preferred bridges are one or two carbon atoms. It is noted that abridge always converts a monocyclic ring into a tricyclic ring. When aring is bridged, the substituent recited for the ring can also bepresent on the bridge. Fused (e.g., naphthyl and tetrahydronaphthyl) andspiro rings are also included.

As used herein, the term “heterocycle” means, unless otherwise stated, astable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclicor tricyclic ring (recognizing that rings with certain numbers ofmembers cannot be bicyclic or tricyclic, e.g., a 3-membered ring canonly be a monocyclic ring), which is saturated, unsaturated (includingpartially and fully unsaturated), or aromatic, and consists of carbonatoms and one or more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen,and sulfur, and including any bicyclic or tricyclic group in which anyof the above-defined heterocyclic rings is fused to a second ring (e.g.,a benzene ring). The nitrogen and sulfur heteroatoms can optionally beoxidized (i.e., N→O and S(O)_(p), where p=1 or 2). When a nitrogen atomis included in the ring it is either N or NH, depending on whether ornot it is attached to a double bond in the ring (i.e., a hydrogen ispresent if needed to maintain the tri-valency of the nitrogen atom). Thenitrogen atom can be substituted or unsubstituted (i.e., N or NR whereinR is H or another substituent, as defined). The heterocyclic ring can beattached to its pendant group at any heteroatom or carbon atom thatresults in a stable structure. The heterocyclic rings described hereincan be substituted on carbon or on a nitrogen atom if the resultingcompound is stable. A nitrogen in the heterocycle can optionally bequaternized. It is preferred that the total number of S and O atoms inthe heterocycle is not more than 1. Bridged rings are also included inthe definition of heterocycle. A bridged ring occurs when one or moreatoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogenatoms. Preferred bridges include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring can also be present on the bridge.Spiro and fused rings are also included.

As used herein, the term “aromatic heterocycle” or “heteroaryl” isintended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-memberedmonocyclic or bicyclic aromatic ring (recognizing that rings withcertain numbers of members cannot be a bicyclic aromatic, e.g., a5-membered ring can only be a monocyclic aromatic ring), which consistsof carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen,oxygen, and sulfur. In the case of bicyclic heterocyclic aromatic rings,only one of the two rings needs to be aromatic (e.g.,2,3-dihydroindote), though both can be (e.g., quinoline). The secondring can also be fused or bridged as defined above for heterocycles. Thenitrogen atom can be substituted or unsubstituted (i.e., N or NR whereinR is H or another substituent, as defined). The nitrogen and sulfurheteroatoms can optionally be oxidized (i.e., N→O and S(O)_(p), wherep=1 or 2). It is to be noted that total number of S and O atoms in thearomatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, befizimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinotinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl.1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for administrationto a human, e.g., use in contact with the tissues of human beings andanimals without excessive toxicity, irritation, allergic response, orother problem or complication, commensurate with a reasonablebenefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from 2-acetoxybenzoic,2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic,bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic,glycollyarsanilic, bexylresorcinic, hydrabamic, hydrobromic,hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic,lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic,succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,USA, p. 1445 (1990).

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds of the present invention can be delivered in prodrug form.Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are Intended to include anycovalently bonded carriers that release an active parent drug of thepresent invention in vive when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate, and benzoate derivatives ofalcohol and amine functional groups in the compounds of the presentinvention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

As used herein, “treating” or “treatment” means the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting its development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

As used herein, “mammal” refers to human and non-human patients.

As used herein, the term “therapeutically effective amount” refers to acompound, or a combination of compounds, of the present inventionpresent in or on a recipient in an amount sufficient to elicitbiological activity, for example, anti-microbial activity, anti-fungalactivity, anti-viral activity, anti-parasitic activity, and/oranti-proliferative activity. The combination of compounds is preferablya synergistic combination. Synergy, as described, for example, by Chouand Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs whenthe effect of the compounds when administered in combination is greaterthan the additive effect of the compounds when administered alone as asingle agent. In general, a synergistic effect is most clearlydemonstrated at sub-optimal concentrations of the compounds. Synergy canbe in terms of lower cytotoxicity, increased anti-proliferative and/oranti-infective effect, or some other beneficial effect of thecombination compared with the individual components.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present invention also consistessentially of, or consist of the recited components, and that theprocesses of the present invention also consist essentially of, orconsist of; the recited processing steps. Further, it should beunderstood that the order of steps or order for performing certainactions are immaterial so long as the invention remains operable.

Moreover, two or more stops or actions can be conducted simultaneously.

2. COMPOUNDS OF THE INVENTION

The invention provides a compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrugthereof, wherein:

T is a 14- or 15-membered macrolide connected via a macrocyclic ringcarbon atom;

R¹ and R³ independently are selected from: (a) H; (b) a C₁₋₆ alkylgroup; (c) a C₂₋₄ alkenyl group; (d) a C₂₋₆ alkynyl group; (e) —C(O)R⁵;(f) —C(O)OR⁵; (g) —C(O)—NR⁴R⁴; (h) —C(S)R⁵; (i) —C(S)OR⁵; (j) C(O)SR⁵;or (k) —C(S)—NR⁴R⁴;

R² is hydrogen or —OR¹²;

A is selected from: (a) a C₁₋₆ alkyl group, (b) a C₂₋₆alkenyl group, (c)a C₂₋₆ alkynyl group, (d) a C₃₋₁₂ saturated, unsaturated, or aromaticcarbocycle, (e) a 3-12 membered saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from nitrogen,oxygen, and sulfur; wherein 0-2 carbon atoms in any of (a)-(c) of Aimmediately above optionally is replaced by a moiety selected from O,S(O)_(p), and NR⁵, and each of the groups (a)-(e) immediately aboveoptionally is substituted with one or more R⁵ groups;

G is selected from: (a) —B′ and (b) —B′—Z—B″, wherein each B′ and B″ isindependently selected from (aa) an aryl group, (bb) a heteroaryl group,(cc) a biaryl group, (dd) a fused bicyclic or tricyclic saturated,unsaturated or aromatic ring system optionally containing one or moreheteroatoms selected from nitrogen, oxygen, and sulfur, (ee) a 3-10membered saturated or unsaturated heterocycle containing one or moreheteroatoms selected from nitrogen, oxygen, and sulfur, (ff) a 3-10membered saturated, or unsaturated carbocycle, wherein each (aa)-(ff)optionally is substituted with one or more R¹¹ or R^(11a) groups; and Zis selected from (aa) a single bond, (bb) a C₁₋₆ alkyl group, (cc) aC₂₋₆ alkenyl group, (dd) a C₂₋₆ alkynyl group, (ee) —C(O)—, (f) —C(O)O—,(gg) —C(O)NR⁴—, (hh) —C(═NR⁴)—, (ii) —C(═NR⁴)O—, (jj) —C(═NR⁴)NR⁴—, (kk)—S(O)_(p)—, (ll) —OC(O)—, (mm) —C(S)—, (nn) —C(S)NR⁴—, (oo) —C(NR⁴)S—,(pp) —C(O)S—, (qq) —O—, (rr) —NR⁴—, (ss) —NR⁴C(O)—, (tt) —OC(NR⁴)—, (uu)—NC(NR⁴)—, (vv) —C(S)O—, (ww) —SC(O)—, (xx) —OC(S)— or (yy) —S(O)_(p)—;

R⁴, at each occurrence, independently is selected from (a) H, (b) a C₁₋₆alkyl group, (c) a C₂₋₆ alkenyl group, (d) a C₂₋₆ alkynyl group, (e) aC₆₋₁₀ saturated, unsaturated, or aromatic carbocycle, (f) a 3-12membered saturated, unsaturated, or aromatic heterocycle containing oneor more heteroatoms selected from nitrogen, oxygen, and sulfur, (g)—C(O)—C₁₋₆ alkyl, (h) —C(O)—C₂₋₆ alkanyl, (i) —C(O)—C₂₋₆ alkynyl,

(j) —C(O)—C₆₋₁₀ saturated, unsaturated, or aromatic carbocycle, (k)—C(O)-3-12 membered saturated, unsaturated, or aromatic heterocyclecontaining one or more heteroatoms selected from nitrogen, oxygen, andsulfur, (l) —C(O)O—C₁₋₆ alkyl, (m) —C(O)O—C₂₋₆ alkenyl, (n) —C(O)O—C₂₋₆alkynyl, (o) —C(O)O—C₆₋₁₀ saturated, unsaturated, or aromaticcarbocycle, p) —C(O)O-3-12 membered saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from nitrogen,oxygen, and sulfur, and q) —C(O)NR⁶R⁶, wherein any of (b)-(p) of R⁴, asdefined above, optionally is substituted with one or more R⁵ groups, oralternatively, NR⁴R⁴ forms a 3-7 membered saturated, unsaturated oraromatic ring including the nitrogen atom to which the R⁴ groups arebonded, wherein the ring is optionally substituted at a position otherthan the nitrogen atom to which the R⁴ groups are bonded, with one ormore moieties selected from O, S(O)_(p), N, and NR⁸;

R⁵ is selected from (a) R⁷, (b) a C₁₋₈ alkyl group, (c) a C₂₋₈ alkenylgroup, (d) a C₂₋₈ alkynyl group, (e) a C₃₋₁₂ saturated, unsaturated, oraromatic carbocycle, and (f) a 3-12 membered saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromnitrogen, oxygen, and sulfur, or two R⁵ groups, when present on the samecarbon atom can be taken together with the carbon atom to which they areattached to form a spiro 3-6 membered carbocyclic ring or heterocyclicring containing one or more heteroatoms selected form nitrogen, oxygen,and sulfur; wherein any of (b)-(f) of R⁵ as defined above optionally issubstituted with one or more R⁷ groups;

R⁶, at each occurrence, independently is selected from (a) H, (b) a C₁₋₆alkyl group, (c) a C₂₋₆ alkenyl group, (d) a C₂₋₄ alkynyl group, (e) aC₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, and (f) a 3-10membered saturated, unsaturated, or aromatic heterocycle containing oneor more heteroatoms selected from nitrogen, oxygen, and sulfur, whereinany of (b)-(f) of R as defined above optionally is substituted with oneor more moieties selected from (as) a carbonyl group, (bb) a formylgroup, (co) F, (dd) Cl, (ee) Br, (fi) I, (gg) CN, (hh) NO₂, (ii) —OR⁸,(jj) —S(O)R⁸, (kk) —C(O)R⁸, (ll) —C(O)OR⁸, (mm) —OC(O)R⁸, (nn)—C(O)NR⁸R⁸, (oo) —OC(O)NR⁸R⁸, (pp) —C(—NR⁸)R⁸, (qq) —C(R⁸)(R⁸)OR⁸, (rr)—C(R⁸)₂OC(O)R⁸, (ss) —C(R⁸)(OR)(CH₂)_(r)NR⁸R⁸, (tt) —NR⁸R⁸, (uu)—NR⁸OR⁸, (vv) —NR⁸C(O)R⁸, (ww) —NR⁸C(O)OR⁸, (xx) —NR⁴C(O)NR⁸R⁸, (yy)—NR⁸S(O)_(r)R⁸, (zz) —C(OR⁸)(OR⁸)R⁸, (ab) —C(R⁸)₂NR⁸R⁸, (ac) —NR⁸, (ad)—C(S)NR⁸R⁸, (ae) —NR⁸C(S)R⁸, (af) —OC(S)NR⁸R⁸, (ag) —NR⁸C(S)OR⁸, (ah)—NR⁸C(S)NR⁸R⁸, (ai) —SC(O)R⁸, (aj) a C₁₋₈ alkyl group, (ak) a C₂₋₈alkenyl group, (al) a C₂₋₈ alkynyl group, (am) a C₁₋₈ alkoxy group, (an)a C₁₋₈ alkylthio group, (so) a C₁₋₈ acyl group, (ap) —CF₃, (aq) —SCF₃,(ar) a C₃₋₁₀ saturated, unsaturated, or aromatic carbocyle, and (as) a3-10 membered saturated, unsaturated, or aromatic heterocycle containingone or more heteroatoms selected from nitrogen, oxygen, and sulfur, oralternatively, NR⁶R⁶ forms a 3-10 membered saturated, unsaturated oraromatic ring including the nitrogen atom to which the R⁶ groups areattached wherein the ring is optionally substituted at a position otherthan the nitrogen atom to which the R⁶ groups are bonded, with one ormore moieties selected from O, S(O)_(p), N, and NR⁸; or alternatively,CR⁶R⁶ forms a carbonyl group;

R⁷, at each occurrence, is selected from (a) H, (b) ═O, (c) F, (d) Cl,(e) Br, (f) I, (g) —CF₃, (h) —CN, (i) —N₃ (j) —NO₂, (k)—NR⁶(CR⁶R⁶)_(t)R⁹, (l) —OR⁹, (m) —S(O)_(p)C(R⁶R⁶)_(t)R⁹, (n)—C(O)(O)CR⁶R⁶)_(t)R⁹, (o) —OC(O)(CR⁶R⁶)_(t)R⁹, (p) —SC(O)(CR⁶R⁶)_(r)R⁹,(q) —C(O)O(CR⁶R⁶)_(t)R⁹, (r) —NR⁴C(O)(CR⁶R⁶)_(t)R⁹, (s)—C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (t) —C(═NR⁶)(CR⁶R⁶)_(t)R⁹, (u)—C(═NNR⁶R⁶)(CR⁶R⁶)_(t)R⁹, (v) —C(—NNR⁴C(O)R⁶)CR⁶R⁶)_(t)R⁹, (w)—C(═NOR)(CR⁶R⁶)_(t)R⁹, (x) —NR⁶C(O)O(CR⁶R⁶)_(t)R⁹, (y)—OC(O)NR(CR⁶R⁶)_(t)R⁹, (z) —NR⁶C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (aa)—NR⁶S(O)_(p)(CR⁶R⁶)_(t)R⁹, (bb) —S(O)_(p)NR⁶ (CR⁶R⁶)_(t)R⁹, (cc)—NR⁶S(O)_(p)NR⁶(CR⁶R⁶)_(t)R⁹, (dd) —NR⁶R⁶, (ee) —NR⁶(CR⁶R⁶), (ff) —OH,(gg) —NR⁶R⁶, (hh) —OCH₃, (ii) —S(O)_(p)R⁶, (jj) —NC(O)R⁶, (kk) a C₁₋₆alkyl group, (ll) a C₂₋₆ alkonyl group, (mm) a C₂₋₆ alkynyl group, (nn)—C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, and (oo) 3-10membered saturated, unsaturated, or aromatic heterocycle containing oneor more heteroatoms selected from nitrogen, oxygen, and sulfur, whereinany of (kk)-(oo) of R⁷ as defined above optionally is substituted withone or more R⁹ groups; or alternatively, two R⁷ groups can form—O(CH₂)_(u)O—;

R⁸ is selected from (a) R⁵, (b) H, (c) a C₁₋₆ alkyl group, (d) a C₂₋₆alkenyl group, (e) a C₂₋₆ alkynyl group, (f) a C₃₋₁₀ saturated,unsaturated, or aromatic carbocycle, (g) a 3-10 membered saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from nitrogen, oxygen, and sulfur, (h) —C(O)—C₁₋₆ alkyl, (i)—C(O)—C₁₋₆ alkenyl, (j) —C(O)—C₁₋₆ alkynyl, (k) —C(O)—C₃₋₁₀ saturated,unsaturated, or aromatic carbocycle, and (l) —C(O)-3-10 memberedsaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of(c)-(k) of R⁸ as defined above optionally is substituted with one ormore moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I,(ff) CN, (gg) NO₂, (hh) OH, (ii) NH₂, (jj) NH(C₁₋₆ alkyl), (kk) N(C₁₋₆alkyl)₂, (ll) a C₁₋₆ alkoxy group, (mm) an aryl group, (nn) asubstituted aryl group, (oo) a heteroaryl group, (pp) a substitutedheteroaryl group, and qq) a C₁₋₆ alkyl group optionally substituted withone or more moieties selected from an aryl group, a substituted arylgroup, a heteroaryl group, a substituted heteroaryl group, F, Cl, Br, I,CN, NO₂, CF₃, SCF₃, and OH;

R⁹, at each occurrence, independently is selected from (a) R¹⁰, (b) aC₁₋₆ alkyl group, (c) a C₂₋₆ alkenyl group, (d) a C₂₋₆ alkynyl group, e)a C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, and f) a 3-10membered saturated, unsaturated, or aromatic heterocycle containing oneor more heteroatoms selected from nitrogen, oxygen, and sulfur, whereinany of (b)-(f) of R⁹ as defined above optionally is substituted with oneor more R¹⁰ groups;

R¹⁰, at each occurrence, independently is selected from (a) H, (b) ═O,(c) F, (d) Cl, (e) Br, (f) I, (g) —CF₃, (h) —CN, (i) —NO₂, j) —NR⁶R⁶,(k) —OR⁶, (l) —S(O)_(p)R⁶, (m) —C(O)R⁶, (n) —C(O)OR⁶, (o) —OC(O)R⁶, (p)NR⁶C(O)R⁶, (q) —C(O)NR⁶R⁶, (r) —C(═NR⁶R⁶, (s) —NR⁶C(O)NR⁶R⁶, (t)—NR⁶S(O)_(p)R⁶, (u) —S(O)_(p)NR⁶R⁶, (v) —NR⁶S(O)_(p)NR⁶R⁶, (w) a C₁₋₆alkyl group, (x) a C₂₋₆ alkenyl group, (y) a C₂₋₆ alkynyl group, (z) aC₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, and (aa) a 3-10membered saturated, unsaturated, or aromatic heterocycle containing oneor more heteroatoms selected from nitrogen, oxygen, and sulfur, whereinany of (w)-(aa) of R¹⁰ as defined above optionally is substituted withone or more moieties selected from R⁶, F, Cl, Br, I, CN, NO₂, —OR, —NH₂,—NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthiogroup, and a C₁₋₆ acyl group;

R¹¹ and R^(11a) a each occurrence, independently is selected from (a) acarbonyl group, (b) a formyl group, (c) F, (d) Cl, (e) Br, (f) I, (g)CN, (h) NO₂, (i) OR⁸, (j) —S(O)_(p)R⁸, (k) —C(O)R⁸, (l) —C(O)OR⁸, (m)—OC(O)R⁸, (n) —C(O)NR⁸R⁸, (o) —OC(O)NR⁸R⁸, (p) —C(═NR)R⁸, (q)—C(R⁸)(R⁸)OR⁸, (r) —C(R⁸)OC(O)R⁸, (s) —C(R⁸)(OR⁸)(CH₂)_(r)NR⁸R⁸, (t)—NR⁸R⁸, (u) —NR⁸OR⁸, (v) —NR⁸C(O)R⁸, (w) —NR⁸C(O)OR⁸, (x) —NR⁴C(O)NR⁸R⁸,(y) —NR⁸S(O)_(p)R⁸, (z) —C(OR⁸)(OR⁸)R⁸, (aa) —C(R⁸)NR⁸R⁸, (bb) —NR⁸,(cc) —C(S)NR⁸R⁸, (dd) —NR⁸C(S)R⁸, (ee) —OC(S)NR⁸R⁸, (B) —NR⁸C(S)OR⁸,(gg) —NR⁶ (S)NR⁶R⁶, (hh) —SC(O)R⁸, (ii) a C₁₋₈ alkyl group, (jj) a C₂₋₈alkenyl group, (kk) a C₂₋₈ alkynyl group, (ll) a C₁₋₈ alkoxy group, (mm)a C₁₋₈ alkylthio group, (nn) a C₁₋₈ acyl group, (oo) a C₃₋₁₀ saturated,unsaturated, or aromatic carbocycle, and (pp) a 3-10 membered saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from nitrogen, oxygen, and sulfur, wherein (ii)-(kk) optionallyare substituted with one or more R⁵ groups;

R¹² is selected from (a) H, (b) a C₁₋₆ alkyl group, (c) a C₂₋₆ alkenylgroup, (d) a C₂₋₆ alkynyl group, (e) —C(O)R⁵, (f) —C(O)OR, (g)—C(O)—NR⁴R⁴, (h) —C(S)R⁵, (i) —C(S)OR⁵, (j) —C(O)SR⁵, (k) —C(S)—NR⁴R⁴,(l) a C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, or (m) a3-10 membered saturated, unsaturated, or aromatic heterocycle containingone or more heteroatoms selected from nitrogen, oxygen, and sulfur, (n)a —(C₁₋₆ alkyl) —C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle,Or (o) a —(C₁₋₆ alkyl)-3-10 membered saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from nitrogen,oxygen, and sulfur, wherein (a)-(d) and (l)-(o) of R¹² as defined aboveoptionally are substituted with one or more R⁵ groups;

p at each occurrence is 0, 1, or 2;

r at each occurrence is 0, 1, or 2;

t at each occurrence is 0, 1, or 2;

and u at each occurrence is 1, 2, 3, or 4.

In the present invention, the macrolide, “T” is defined to Includevarious 14- and 15-membered ring systems, which can contain one or moreheteroatams. Also, as defined herein, the macrolide, “T” is connectedvia a macrocyclic ring carbon atom”, which means that the connection orbond is made to a carbon atom on the 14- or 15-membered ring of themacrolide moiety. The macrolide can include further substituents,including ring substituents. For example, the substituent designated asR¹⁰³ (as defined below) can in certain embodiments be a sugar moiety,e.g. a cladinose sugar, or the substituents such as R¹⁰⁴ and R¹⁰⁵ (asdefined below) are taken together in certain embodiments to form abridged bicyclic ring system with the macrolide ring, or thesubstituents R¹⁰⁵ and R¹⁰⁶ (as defined below), are taken together incertain embodiments to form a fused bicyclic ring system with themacrolide ring, or the substituents or components M, R¹⁰⁵ and R¹⁰⁶ aretaken together to form a fused tricyclic ring system with the macrolidering, etc. It is also recognized in the present invention that “T” isdepicted as being connected to a 6-membered ring, for example in certainembodiments a desosamine sugar ring.

The invention also provides a compound according to claim 1, having thestructure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrugthereof wherein A, G, T, R¹, R² and R³ are as defined above.

In the compounds described above, A is, for example, is a C₁₀₆ alkylgroup, wherein 0-2 carbon atoms in any of the C₁₋₆ alkyl groupoptionally is replaced by a moiety selected from 0, S(O)_(p), and NR⁴,and the C₁₋₆ alkyl group optionally is substituted with one or more R⁵groups. In compounds where A is, for example, a C₁₋₆ alkyl group, A-g isselected from the group consisting of: (a) —(CH₂)₂-G, (b) —(CH₂)₃-G, (c)—(CH₂)₄-G, (d) —(CH₂)₃O-G, (e) —(CH₂)₃—NH-G, (f) —CH(CH₂F)CH₂NHC(O)-G,(g) —CH(CH₂F)CH₂NHS(O)₂-G, (h) —(CH₂)₂NHS(O)₂-G, (i) —(CH₂)₂NHCH₂-G, (j)—(CH₂)₃S-G, (k) —(CH₂)₃S(O)₂-G, (l) —(CH₂)₂N(CH₃)CH₂-G, (m)—(CH₂)₂NHCH₂-G, (n) —CH₂CH(OH)CH₂O-G, (o) —CH₂CHFCH₂O-G, and (p)—CH₂CH(CH₃)CH₂O-G. In compounds where A, for example, is a C₁₋₆ alkylgroup, A-G is also selected from the group consisting of (a) —(CH₂)-G,(b) —(CH₂)O-G, (c) —(CH₂)₃—NH-G, (d) —CH(CH₂F)CH₂NHC(O)-G, (e)—C(CH₂F)CH₂NHS(O)₂-G, (f) —(CH₂)₂NHS(O)-G, (g) —(CH₂)₂NHCH₂-G, (h)—(CH₂)₃S-G, (i) —(CH₂)₃S(O)₂-G, (j) —(CH₂)₂N(CH₃)CH₂-G, (k)—(CH₂)₂NHCH₂-G, (l) —CH₂CH(OH)CH₂O-G, (m) —CH₂CHFCH₂O-G, and (n)—CH₂CH(CH₃)CH₂O-G.

In the compounds described above, -A-G is also selected from the groupconsisting of:

(a) —CH₂-G, (b) —(CH₂)₂-G, (c) —(CH₂)₃-G, (d) —(CH₂)₄-G, (e)—CH₂O(CH₂)₂-G (f) —(CH₂)₂OCH₂-G, (g) —(CH₂)₃O-G, (h) —CH₂NR⁵(CH₂)₂-G,(i) —(CH₂)₂NR⁵CH₂-G, (j) —(CH₂)₃—NR⁵-G, (m) —SO—(CH₂)₃-G, (n)—SO₂—(CH₂)₃-G, (o) —CH₂S(O)_(p)(CH₂)₂-G, (o) —(CH₂)₂S(O)_(p)CH₂-G, (p)—(CH₂)₃S(O)_(p)-G, (q) —CO(CH₂)₃-G, (r) —CH₂CO(CH₂)₂—, (s)—(CH₂)₂COH₂-G, (t) —(CH₂)₃CO-G, (u) —CH₂CH(OR⁹)(CH₂)₂—O, (v)—(CH₂)₂CH(OR⁹)CH₂-G,(w) —(CH₂)₃CH(OR⁹)-G, (x) —CHOR⁵(CH₂)₃-G, (y) —CH₂CHOR⁹(CH₂)₂-G, (z)—(CH₂)₂CHOR⁹CH₂-G, (aa) —(CH₂)₃CHOR⁹-G, (bb) —CONR⁵(CH₂)₂-G, (cc)—CH₂CONR⁵CH₂-G,(dd) —(CH₂)₂CONR⁵-G, (ee) —CH₂NR⁵COCH₂-G, (ff) —(CH₂)₂NR⁵CO-G, (gg)—S(O)NR⁵ (CH₂)₂-G, (hh) —S(O)₂NR⁵(CH₂)₂-G, (ii) —CH₂S(O)_(p)NR⁵CH₂-G,(jj) —(CH₂)₂S(O)_(p)NR⁸-G, (kk) NR⁵S(O)_(p)(CH₂)₂-G, (ll)—CH₂NR⁵S(O)_(p)CH₂-G, (mm) —(CH₂)₂NR⁵S(O)_(p)-G, (nn) —CH₂CH(CH₃)CH₂O-G,(oo) —CH₂CH(OR⁹)CH₂O-G,

wherein p is 0, 1, or 2, and R⁵ and R⁹ are independently C₁₋₆ alkyl,optionally substituted with fluorine, and wherein in any of theforegoing (a) through (tt) one or more hydrogens on a carbon atom isoptionally replaced with fluorine.

In the compounds described above, -A-G is also selected from the groupconsisting of:

(a) —(CH₂)₄-G, (b) —(CH₂)₂OCH₂-G, (c) —(CH₂)₃O-G, (d) —(CH₂)₄NR⁵CH₂-G,(e) —(CH₂)₃—NR⁵-G, (f) —(CH₂)₃S(O)_(p)-G, (g) —(CH₂)₃CO-G, (h)—CH₂CH(OR)CH₂O-G, (i) —CH₂CH(CH₃)CH₂O-G, (j) —(CH₂)₂NR⁵CO-G, (k)—(CH₂)₂NR⁵S(O)_(p)-G,

wherein p is 0, 1, or 2, and R⁵, and wherein in any of the foregoing (a)through (n) one or more hydrogens on a carbon atom is optionallyreplaced with fluorine.

In the compounds described above, -A-G is also selected from the groupconsisting of: (a) —(CH₂)₄—O, and (b) —(CH₂)₃O-G.

In the compounds described above, R¹ is, for example, H. In thecompounds described above, R² is, e.g., H. In the compounds describedabove, R³ is, e.g., C₁₋₆ alkyl. In the compounds described above, R³ is,e.g., methyl. In the In the compounds described above, G is, e.g., B′.In the compounds described above, B′ is selected from, for example: (a)an aryl group, (b) a heteroaryl group, (c) a biaryl group, and (d) afused bicyclic or tricyclic unsaturated or aromatic ring systemoptionally containing one or more carbonyl groups and one or moreheteroatoms selected from nitrogen, oxygen, and sulfur, wherein each(a)-(d) of B′ as defined herein optionally is substituted with one ormore R¹¹ groups.

In the compounds described above, G is, e.g., —B′—Z—B″. In thesecompounds where G is —B′—Z—B″, B′ and B″ are, for example, independentlyselected from: (a) an aryl group, (b) a heteroaryl group, (c) a biarylgroup, and (d) a fused bicyclic or tricyclic unsaturated or aromaticring system optionally containing one or more carbonyl groups and one ormore heteroatoms selected from nitrogen, oxygen, and sulfur, whereineach (a)-(d) of B′ and B″ as defined herein optionally is substitutedwith one or more R¹¹ groups, and Z is selected from (aa) a single bond,(bb) —O—, (cc) —NR⁴—, (dd) —C(O)—, (ee) —C(S)—, (ff) —S(O)_(p)—, and(gg) a C₁₋₆ alkyl.

The invention also provides a compound according having the structure

or a pharmaceutically acceptable slat, ester, N-oxide, or prodrugthereof wherein T is a 14- or 15-membered macrolide connected via amacrocyclic ring carbon atom;

R¹ and R³ independently are selected from: (a) H; (b) a C₁₋₆ alkylgroup; (c) a C₂₋₆ alkenyl group; (d) a C₂₋₆ alkynyl group; (e) —C(O)R⁵;(f) —C(O)OR⁵; (g) —C(O)—NR⁴R⁴; (h) —C(S)R⁵; (i) —C(S)OR⁵; (j) —C(O)SR⁵;or (k) —C(S)—NR⁴R⁴;

R² is hydrogen or —OR¹², where R¹² is as defined above;

A is selected from: (a) a C₁₋₆ alkyl group, (b) a C₂₋₆ alkenyl group;(c) a C₂₋₆ alkynyl group; wherein 0-2 carbon atoms in any of (a)-(c) ofA, as defined above, optionally is replaced by a moiety selected from 0,S(O)_(p), and NR⁴, and each of the groups (a)-(c) of A, as definedabove, optionally is substituted with one or more R⁵ groups as definedabove;

B″ is selected from (as) an aryl group, (bb) a heteroaryl group, (cc) abiaryl group, (dd) a fused bicyclic or tricyclic saturated, unsaturatedor aromatic ring system optionally containing one or more heteroatomsselected from nitrogen, oxygen, and sulfur, (ee) a 3-10 memberedsaturated or unsaturated heterocycle containing one or more heteroatomsselected from nitrogen, oxygen, and sulfur, (if) a 3-10 memberedsaturated, or unsaturated carbocycle, wherein each (aa)-(ff) optionallyis substituted with one or more R¹¹ or R^(11a), groups; and Z isselected from (aa) a single bond, (bb) a C₁₋₆ alkyl group, (cc) a C₂₋₆alkenyl group, (dd) a C₂₋₆ alkynyl group, (ee) —C(O)—, (ff) —C(O)O—,(gg) —C(O)NR⁴—, (hh) —C(═NR⁴)—, (ii) —C(═NR⁴)O—, (jj) —C(═NR⁴)NR⁴—, (kk)—S(O)_(p)—, (ll) —OC(O)—, (mm) —C(S)—, (nn) —C(S)NR⁴—, (oo) —C(NR⁴)S—,(pp) —C(O)S—, (qq) —O—, (rr) —NR⁴—, (ss) —NR⁴C(O)—, (tt) —OC(NR⁴)—, (uu)—NC(NR⁴)—, (vv) —C(S)O—, (ww) —SC(O)—, (xx) —OC(S)— or (yy) —S(O)_(p)—;

R¹¹ and R^(11a) at each occurrence, independently is selected from (a) acarbonyl group, (b) a formyl group, (c) F, (d) Cl, (e) Br, (f) I, (g)CN, (h) NO₂, (i) OR⁸ (as defined above) (j) —S(O)_(p)R⁸, (k) —C(O)R⁸,(l) —C(O)OR⁸, (m) —OC(O)R⁸, (n) —C(O)NR⁸R⁸, (o) —OC(O)NR⁸R⁸, (p)—C(═NR⁸)R⁸, (q) —C(R⁸)(R⁸)OR⁸, (r) —C(R⁸)₂OC(O)R⁸, (s)—C(R⁸)(OR⁸)(CH₂)_(r)NR⁸R⁸, (t) —NR⁸R⁸, (u) —NR⁸OR⁸, (v) —NR⁸C(O)R⁸, (w)—NR⁸C(O)OR⁸, (x) —NR⁸C(O)NR⁸R⁸, (y) —NR⁸S(O)R⁸, (z) —C(OR⁸)(OR⁸)R⁸, (aa)—C(R⁸)NR⁸R⁸, (bb) —NR⁸, (cc) —C(S)NR⁸R⁸, (dd) —NR⁸C(S)R⁸, (ee)—OC(S)NR⁸R⁸, (ff) —NR⁸C(S)OR⁸, (gg) —NR⁸C(S)NR⁸R⁸, (hh) —SC(O)R⁸, (ii) aC₁₋₈ alkyl group, (jj) a C₂₋₈ alkenyl group, (kk) a C₂₋₈ alkynyl group,(ll) a C₁₋₈ alkoxy group, (mm) a C₁₋₈ alkylthio group, (nn) a C₁₋₈ acylgroup, (oo) a C₁₋₁₀ saturated, unsaturated, or aromatic carbocycle, and(pp) a 3-10 membered saturated, unsaturated, or aromatic heterocyclecontaining one or more heteroatoms selected from nitrogen, oxygen, andsulfur, wherein (ii)-(kk) optionally are substituted with one or mom R⁵groups, as defined above.

In compounds having this structure, A is, for example, a C₁₋₆ alkylgroup, wherein 0-2 carbon atoms in any of the C₁₋₆ alkyl groupoptionally is replaced by a moiety selected from O, S(O)_(p), and NR⁴,and the C₁₋₆ alkyl group optionally is substituted with one or more R⁵groups as defined above.

In the compounds described above, -A is, for example, (a) —CH₂—, (b)—(CH₂)₂—, (c) —(CH₂)₃—, (d) —(CH₂)₄—, (e) —CH₂O(CH₂)₂—, (f)—(CH₂)₂OCH₂—, (g) —(CH₂)₃O—, (h) —CH₂NR⁵(CH₂)₂—, (i) —(CH₂)₂NR⁵CH₂—, (j)—(CH₂)₃—NR⁵—, (m) —SO—(CH₂)₃—, (n) —SO₂—(CH₂)₃—, (o)—CH₂S(O)_(p)(CH₂)₂—, (o) —(CH₂)₂S(O)_(p)CH—, (p) —(CH₂)₃S(O)_(p)—, (q)—CO(CH₂)₃—, (r) —CH₂CO(CH₂)₂—, (s) —(CH₂)₂COCH₂—, (t) —(CH₂)_(r)CO—, (u)—CH₂CH(OR⁹)(CH₂)₂—, (v) —(CH₂)₂CH(OR)CH₂—, (w) —(CH₂)₃CH(OR⁹)—, (x)—CHOR⁵ (CH₂)₃—, (y) —CH₂CHOR⁹ (CH₂)₂—, (z) —(CH₂)₂CHOR⁴CH₂—, (aa)—(CH₂)₃CHOR⁹—, (bb) —CONR⁵(CH₂)₂—, (cc) —CH₂CONR⁵CH₂—, (dd)—(CH₂)₂CONR⁵—, (ee) —CH₂NR⁵COCH₂—, (ff) —(CH₂)₂NR⁵CO—, (gg) —S(O)NR⁵(CH₂)₂—, (hh) —S(O)₂NR⁵(CH₂)₂—, (ii) —CH₂S(O)_(p)NR⁵CH₂—, (jj)—(CH₂)₂S(O)_(p)NR⁵—, (kk) —NR⁵S(O)_(p)(CH₂)₂—, (ll) —CH₂NR⁵S(O)_(p)CH₂—,(mm) —(CH₂)₂NR⁵S(O)_(p)—, (nn) —CH₂CH(CH₃)CH₂O—, (oo) —CH₂CH(OR⁹)CH₂O—,

(uu) —(CH₂)₃—NH—, (vv) —CH(CH₂F)CH₂NHC(O)—, (ww) —CH(CH₂F)CH₂NHS(O)₂—,(xx) —(CH₂)NHS(O)₂—, (yy) —(CH₂)₂NHCH₂—, (z) —(CH₂)₃S—, (aaa)—(CH₂)₃S(O)₂—, (bbb) —(CH₂)₂N(CH₃)CH₂—, (ccc) —(CH₂)₂NHCH₂—, (ddd)—CH₂CH(OH)CH₂O—, (eee) —CH₂CHFCH₂O—, and (fff) —CH₂CH(CH₃)CH₂O—, whereinp is 0, 1, or 2, and R¹ and R⁹ are independently C₁₋₆ alkyl, optionallysubstituted with fluorine, and wherein in any of the foregoing (a)through (fff) one or more hydrogens on a carbon atom is optionallyreplaced with fluorine.

The invention also provides a compound having the structure:

or a pharmaceutically acceptable slat, ester, N-oxide, or prodrugthereof wherein A, B″, T, Z, R¹, R², R³, and R¹¹ are as described above.

In compounds having this structure, A is, for example, a C₁₋₆ alkylgroup, wherein 0-2 carbon atoms in any of the C₁₋₆ alkyl groupoptionally is replaced by a moiety selected from O, S(O)_(p), and NR⁴,and the C₁₋₆ alkyl group optionally is substituted with one or more R⁵groups as defined above.

In the compounds described above, -A is, for example, (a) —CH₂—, (b)—(CH₂)₂—, (c) —(CH₂)₃—, (d) —(CH₂)₄—, (e) —CH₂O(CH₂)₃—, (f)—(CH₂)₂OCH₂—, (g) —(CH₂)₃O—, (h) —CH₂NR⁵(CH₂)₂—, (i) —(CH₂)₂NR⁵CH₂—, (j)—(CH₂)₃—NR⁵—, (m) —SO—(CH₂)₃—, (n) —SO₂—(CH₂)₃—, (o)—CH₂S(O)_(p)(CH₂)₂—, (o) —(CH₂)S(O)_(p)CH₂—, (p) —(CH₂)₃S(O)_(p)—, (q)—CO(CH₂)₃—, (r) —CH₂CO(CH₂)—, (s) —(CH₂)₂COCH₂—, (t) —(CH₂)₃CO—, (u)—CH₂CH(OR⁹)(CH₂)₂—, (v) —(CH₂)CH(OR)CH₂—, (w) —(CH₂)₃CH(OR⁹)—, (x)—CHOR⁵(CH₂)₃—, (y) —CH₂CHOR⁹(CH₂)—, (z) —(CH₂)₂CHOR⁹CH₂—, (aa)—(CH₂)₃CHOR⁹—, (bb) —CONR⁵(CH₂)₂—, (cc) —CH₂CONR⁵CH₂—, (dd)—(CH₂)₂CONR⁵—, (ee) —CH₂NR⁴COCH₂—, (ff) —(CH₂)₂NR⁵CO—, (gg)—S(O)NR⁵(CH₂)₂—, (hh) —S(O)₂NR(CH₂)₂—, (ii) —CH₂S(O)_(p)NR⁵CH₂—, (jj)—(CH₂)₂S(O)_(p)NR⁵—, (kk) —NR⁵S(O)_(p)(CH₂)₂—, (ll) —CH₂NR⁵S(O)_(p)CH₂—,(mm) —(CH₂)₂NR⁵S(O)_(p)—, (nn) —CH₂CH(CH₃)CH₂O—, (oo) —CH₂CH(OR⁹)CH₂O—,

(uu) —(CH₂)₃—NH—, (vv) —CH(CH₂F)CH₂NHC(O)—, (ww) —CH(CH₂F)CH₂NHS(O)₂—,(xx) —(C)₂NHS(O)₂—, (yy) —(CH₂)₂NHCH₂—, (zz) —(CH₃)₃S—, (aaa)—(CH₂)₃S(O)₂—, (bbb) —(CH₂)₂N(CH₃)CH₂—, (ccc) —(CH₂)NHCH₂—, (ddd)—CH₂CH(OH)CH₂O—, (eee) —CH₂CHFCH₂O—, and (f) —CH₂CH(CH₃)CH₂O—, wherein pis 0, 1, or 2, and R⁵ and R⁹ are independently C₁₋₆ alkyl, optionallysubstituted with fluorine, and wherein in any of the foregoing (a)through (fff) one or more hydrogens on a carbon atom is optionallyreplaced with fluorine.

For example, in this compound-A is, e.g., selected from: (a) —(CH₂)₂—,(b) —(CH₂)₃—, (c) —(CH₂)₄—, (d) —(CH₂)₃O—, (e) —(CH₂)₃—NH—, (f)—CH(CH₂F)CH₂NHC(O)—, (g) —CH(CH₂F)CH₂NHS(O)₂—, (h) —(CH₂)₂NHS(O)₂—, (i)—CH₂)₂NHCH₂—, (j) —(CH₂)₃S—, (k) —(CH₂)₃S(O)₂—, (l) —(CH₂)₂N(CH₃)CH₂—,(m) —(CH₂)₂NHCH₂—, (n) —CH₂CH(OH)CH₂O—, (o) —CH₂CHFCH₂O—, (p)—CH₂CH(CH₃)CH₂O—, (q) —O—(CH₂)₃—, (r) —CH₂—O—(CH₂)₂—, (s)—(CH₂)₂—O—CH₂—, (t) —NH—(CH₂)₇—, (u) —CH₂—NH—(CH₂)—, and (v)—(CH₂)₂—NH—CH₂—. For example, -A is selected from: (a) —(CH₂)₄—, (b)—(CH₂)₃O—, (c) —(CH₃)₃—NH—, (d) —CH(CH₂F)CH₂NHC(O)—, (e)—CH(CH₂F)CH₂NHS(O)₂—, (t) —(CH₂)₂NHS(O)₂—, (g) —(CH₂)NHCH₂—, (h)—(CH₂)₃S—, (i) —(CH₂)₃S(O)₂—, U) —(CH₂)₂N(CH₃)CH₂—, (k) —(CH₂)₂NHCH₂—,(I) —CH₂CH(OH)CH₂O—, (in) —CH₂CHFCH₂O—, (a) —CH₂CH(CH₃)CH₂O— and (o)—(CH₂)₂—O—CH₂—.

The invention also provides a compound having the structure:

or a pharmaceutically acceptable slat, ester, N-oxide, or prodrugthereof wherein A, B″, T, Z, R¹, R², R³, and R¹¹ are as described above.

In compounds having this structure, A is, for example, a C₁₋₆ alkylgroup, wherein 0-2 carbon atoms in any of the C₁₋₆ alkyl groupoptionally is replaced by a moiety selected from O, S(O)_(p), and NR⁴,and the C₁₋₆ alkyl group optionally is substituted with one or more R⁵groups as defined above.

In this compound, -A is, e.g., selected from: (a) —(CH₂)₂—, (b)—(CH₂)₃—, (c) —(CH₂)₄—, (d) —(CH₂)₃O—, (e) —(CH₂)₃—NH—, (f)—CH(CH₂F)CH₂NHC(O)—, (g) —CH(CH₂F)CH₂NHS(O)₂—, (h) —(CH₂)₂NHS(O)₂—, (i)—(CH₂)₂NHCH₂—, (j) —(CH₂)₃S—, (k) —(CH₂)₃S(O)₂—, (1) —(CH₂)₂N(CH₃)CH—,(m) —(CH₂)₂NHCH₂—, (n) —CH₂CH(OH)CH₂O—, (o) —CH₂CHFCH₂O—, (p)—CH₂CH(CH₃)CH₂O—, (q) —O—(CH₂)₃—, (r) —CH₂—O—(CH₂)₂—, (s)—(CH₂)₂—O—CH₂—, (t) —NH—(CH₂)₃—, (u) —CH₂—NH—(CH₂)₂—, and (v)—(CH₂)₂—NH—CH—. For example, -A is selected from: (a) —(CH₂)—, (b)—(CH₂)₃O—, (c) —(CH₂)₃—NH—, (d) —CH(CH₂F)CH₂NHC(O)—, (e)—CH(CH₂F)CH₂NHS(O)₂—, (f) —(CH₂)₂NHS(O)₂—, (g) —(CH₂)₂NHCH₂—, (h)—(CH₂)₃S—, (i) —(CH₂)₃S(O)₂—, (j) —(CH₂)₂N(CH₃)C₂—, (k) —(CH₂)₂NHCH₂—,(I) —CH₂CH(OH)CH₂O—, (m) —CH₂CHFCH₂O—, (n) —CH₂CH(CH₃)CH₂O— and (o)—(CH₂)₂—O—CH₂—.

The invention also provides a compound having the structure:

or a pharmaceutically acceptable slat, ester, N-oxide, or prodrugthereof wherein A, B″, T, Z, R¹, R², R, and R¹¹ are as described above.

In compounds having this structure, A is, for example, a C₁₋₆ alkylgroup, wherein 0-2 carbon atoms in any of the C₁₋₆ alkyl groupoptionally is replaced by a moiety selected from O, S(O)_(p), and NR⁴,and the C₂₋₆ alkyl group optionally is substituted with one or more R⁵groups as defined above.

In such compounds, -A is, e.g., selected from: (a) —(CH₂)₂—, (b)—(CH₂)—, (c) —(CH₂)₄—, (d) —(CH₂)₃O—, (e) —(CH₂)₃—NH—, (l)—CH(CH₂F)CH₂NHC(O)—, (g) —CH(CH₂F)CH₂NHS(O)₂—, (h) —(CH₂)₂NHS(O)—, (i)—(CH₂) NHCH₂—, (j) —(CH₂)₃S—, (k) —(CH₂)₃S(O)₂—, (1) —(CH₂)₂N(CH₃)CH₂—,(m) —(CH₂)₂NHCH₂—, (n) —CH₂CH(OH)CH₂O—, (o) —CH₂CHFCH₂O—, (p)—CH₂CH(CH₃)CH₂O—, (q) —O—(CH₂)₃—, (r) —CH₂—O—(CH₂)₂—, (s)—(CH₂)₂—O—CH₂—, (t) —NH—(CH₂)₃—, (u) —C₂—NH—(CH₂)₂—, and (v)—(CH₂)₂—NH—CH₂—. For example, -A is selected from: (a) —(CH₂)₄—, (b)—(CH₂)₃O—, (c) —(CH₂)₃—NH—, (d) —CH(CH₂F)CH₂NHC(O)—, (e)—CH(CH₂F)CH₂NHS(O)—, (f) —(CH₂)₂NHS(O)—, (g) —(CH₂)₂NHCH₂—, (h)—(CH₂)₃S—, (i) —(CH₂)₃S(O)₂—, (j) —(CH₂)₂N(CH₃)CH₂—, (k) —(CH₂)₂NHCH₂—,(1) —CH₂CH(OH)CH₂O—, (m) —CH₂CHFCH₂O—, (n) —CH₂CH(CH₃)CH₂O— and (o)—(CH₂)₂—O—CH₂—.

The invention also provides a compound having the structure:

or a pharmaceutically acceptable slat, ester, N-oxide, or prodrugthereof wherein B″, T, Z, R¹, R², and R³ are as described in claim 1.

T is a 14- or 15-membered macrolide connected via a macrocyclic ringcarbon atom;

R¹ and R³ independently are selected from: (a) H; (b) a C₁₋₆ alkylgroup; (c) a C₂₋₆ alkenyl group; (d) a C₂₋₆ alkynyl group; (e) —C(O)R⁵;(f) —C(O)OR⁵; (g) —C(O)—NR⁴R⁴; (h) —C(S)R⁵; (i) —C(S)OR; (i) —C(O)SR⁵;or (k) —C(S)—NR⁴R⁴;

R² is hydrogen or —OR¹² as defined above;

B″ is selected from (aa) an aryl group, (bb) a heteroaryl group, (cc) abiaryl group, (dd) a fused bicyclic or tricyclic saturated, unsaturatedor aromatic ring system optionally containing one or more heteroatomsselected from nitrogen, oxygen, and sulfur, (ee) a 3-10 memberedsaturated or unsaturated heterocycle containing one or more heteroatomsselected from nitrogen, oxygen, and sulfur, (ff) a 3-10 memberedsaturated, or unsaturated carbocycle, wherein each (aa)-(ff) optionallyis substituted with one or more R¹¹ or R^(11a) groups; and Z is selectedfrom (as) a single bond, (bb) a C₁₋₆ alkyl group, (co) a C₂₋₆ alkenylgroup, (dd) a C₂₋₆ alkynyl group, (ee) —C(O)—, (ff) —C(O)O—, (gg)—C(O)NR⁴—, (hh) —C(═NR⁴)—, (ii) —C(═NR⁴)O—, (jj) —C(═NR⁴)NR⁴—, (kk)—S(O)_(p)—, (ll) —OC(O)—, (mm) —C(S)—, (nn) —C(S)NR⁴—, (oo) —C(NR⁴)S—,(pp) —C(O)S—, (qq) —O—, (rr) —NR⁴—, (ss) —NR⁴C(O)—, (tt) —OC(NR⁴)—, (uu)—NC(NR⁴)—, (vv) —C(S)O—, (ww) —SC(O)—, (xx) —OC(S)— or (yy) —S(O)_(p)—.

The invention also provides a compound having the structure:

or a pharmaceutically acceptable slat, ester, N-oxide, or prodrugthereof wherein B″, T, Z, R¹, R², and R³ are as described above.

The invention also provides a compound having the structure:

or a pharmaceutically acceptable slat, ester, N-oxide, or prodrugthereof wherein B″, T, Z, R¹, R², and R³ are as described above.

In certain of the compounds described above, —ZB″ is, e.g., selectedfrom:

wherein R^(11a) is selected from (a) a carbonyl group, (b) a formylgroup, (c) P, (d) Cl, (e) Br, (f) I, (g) CN, (h) NO₂, (i) OR⁸, (j)—S(O)_(p)R⁸, (k) —C(O)R⁸, (l) —C(O)OR⁸, (m) —OC(O)R⁸, (n) —C(O)NR⁸R⁸,(o) —OC(O)NR⁸R⁸, (p) —C(—NR⁸)R⁸, (q) —C(R⁸)(R)OR⁸, (r) —C(R⁸)₂OC(O)R⁸,(s) —C(R⁸)(OR⁸)(CH₂)NR⁸R⁸, (t) —NR⁸R⁸, (u) —NR⁸OR⁸, (v) —NR⁸C(O)R⁸, (w)—NR⁸C(O)OR⁸, (x) —NR⁴C(O)NR⁸R⁸, (y) —NR⁸S(O)_(p)R⁸, (z) —C(OR⁸)(OR⁸)R⁸,(aa) —C(R⁸)₂NR⁸R⁸ (bb) ═NR⁸, (cc) —C(S)NR⁸R⁸, (dd) —NR⁸C(S)R⁸, (ee)—OC(S)NR⁸R⁸, (ff) —NR⁸C(S)OR⁸, (gg) —NR⁴C(S)NR⁸R⁸, (hh) —SC(O)R⁸, (ii) aC₁₋₈ alkyl group, (jj) a C₂₋₈ alkenyl group, (kk) a C₂₋₈ alkynyl group,(ll) a C₁₋₈ alkoxy group, (mm) a C₁₋₈ alkylthio group, (nn) a C₁₋₈ acylgroup, (oo) a C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, and(pp) a 3-10 membered saturated, unsaturated, or aromatic heterocyclecontaining one or more heteroatoms selected from nitrogen, oxygen, andsulfur, wherein (ii)-(kk) optionally are substituted with one or more R⁵groups.

In the compounds described above, T is, for example,

M is selected from: (a) —C((O)—, (b) —CH(—OR¹¹⁴—, (c) —NR¹¹⁴CH₂—, (d)—CH₂—NR¹¹⁴—, (c) —CH(NR¹¹⁴R¹¹⁴)—, (f) —C(═NNR¹¹⁴R¹¹⁴)—, (g)—NR¹¹⁴—C(O)—, (h) —C(O)NR¹¹⁴, (i) —C(═NR¹¹⁴)—, (j) —CR¹¹⁵R¹¹⁵—, and (k)—C(═NOR¹²⁷)—;

-   -   R¹⁰⁰ is selected from (a) H, (b) F, (c) Cl, (d) Br, (e) —SR¹¹⁴,        and (f) C₁₋₆ alkyl, wherein (f) optionally is substituted with        one or more R¹¹⁵ is groups;    -   R¹⁰¹ is selected from: (a) H, (b) Cl, (c) F, (d) Br, (e) I, (f)        —NR¹¹⁴R¹¹⁴, (g) —NR¹¹⁴C(O)R¹¹⁴, (h) —OR¹¹⁴, (i) —OC(O)R¹¹⁴, (j)        —OC(O)OR¹¹⁴, (k) —OC(O)NR¹¹⁴R¹¹⁴, (l) —O—C₁₋₆ alkyl, (m)        —OC(O)—C₁₋₆ alkyl, (n) —OC(O)O—C₁₋₆ alkyl, (o) —OC(O)NR¹¹⁴—C₁₋₆        alkyl, (p) C₁₋₆ alkyl, (q) C₁₋₆ alkenyl, and (r) C₁₋₆ alkynyl,        -   wherein any of (l)-(r) optionally is substituted with one or            more R¹¹⁵ groups;    -   R¹⁰² is H, (b) F, (c) Cl, (d) Br, (e) —SR¹¹⁴, (f) C₁₋₆ alkyl,        wherein (f) optionally is substituted with one or more R¹¹⁵        groups;    -   R¹⁰³ is selected from: (a) H, (b) —OR¹¹⁴, (c) —O—C₁₋₆        alkyl-R¹¹⁵, (d) —OC((O)R¹¹⁴, (e) —OC(O)—C₁₋₆alkyl-R¹¹⁵, (f)        —OC(O)OR¹¹⁴, (g) —OC(O)O—C₁₋₆ alkyl-R¹¹⁵,        -   (h) —OC(O)NR¹¹⁴R¹¹⁴, (i) —OC(O)NR¹¹⁴—C₁₋₆ alkyl-R¹¹⁵, and            (j)

-   -   alternatively, R¹⁰² and R¹⁰³ taken together with the carbon to        which they are attached form (a) a carbonyl group or (b) a 3-7        membered saturated, unsaturated or aromatic carbocyclic or        heterocyclic ring which can optionally be substituted with one        or more R¹¹⁴ groups;    -   alternatively, R¹⁰¹ and R¹⁰³ taken together are a single bond        between the respective carbons to which these two groups are        attached thereby creating a double bond between the carbons to        which R¹⁰⁰ and R¹⁰² are attached;    -   alternatively, R¹⁰¹ and R¹⁰² taken together with the carbons to        which they are attached form a 3-membered saturated, unsaturated        or aromatic carbocyclic or heterocyclic ring which can        optionally be substituted with one or more R¹¹⁴ groups;

R¹⁰⁴ is selected from: (a) H, (b) R¹¹⁴, (c) —C(O)R¹¹⁴(d) —C(O)OR¹¹⁴ (e)—C(O)NR¹¹⁴R¹¹⁴, (f) —C₁₋₆ alkyl-K—R¹¹⁴, (g) —C₂₋₆ alkenyl-K—R¹¹⁴, and(h) —C₂₋₆ alkynyl-K—R¹¹⁴;

K is selected from: (a) —C(O)—, (b) —C(O)O—, (c) —C(O)NR¹¹⁴—, (d)—C(O)OR¹¹⁴)—, (e) —C(═NR¹¹⁴R¹¹⁴)O—, (f) —C(═NR¹¹⁴)NR¹¹⁴—, (g) —OC(O)—,(h) —OC(O)O—, (i) —OC(O)NR¹¹⁴—, (j) —NR¹¹⁴C(O)—, (k) —NR¹¹⁴C(O)O—, (l)—NR¹¹⁴C(O)NR¹¹⁴, (m) —NR¹¹⁴C(═NR¹¹⁴)NR¹¹⁴—, and (o) —S(O)_(p)—;

-   -   alternatively R¹⁰³ and R¹⁰⁴, taken together with the atoms to        which they are bonded, form:

wherein R¹³⁵ and R¹³⁶ are selected from (a) hydrogen, (b) C₁₋₆ alkyl,(c) C₂₋₆ alkenyl, (d) C₂₋₆ alkynyl, (d) C₃₋₁₄ saturated, unsaturated oraromatic carbocycle, (e) 3-14 membered saturated, unsaturated oraromatic heterocycle containing one or more oxygen, nitrogen, or sulfuratoms, (f) F, (g) Br, (h) I, (i) OH, (j) —N₃, wherein (b) through (e)are optionally substituted with one or more R¹¹⁷; or alternatively, R¹³⁵and R¹³⁶ are taken together to form ═O, ═S and —NR¹¹⁴, ═NOR¹¹⁴, ═NR¹¹⁴,and ═N—NR¹¹⁴R¹¹⁴,

wherein V is selected from (a) —(C₁-C₄-alkyl)-, (b) —(C₄-alkenyl)-, (c)O, (d) S, and (e) NR¹¹⁴, wherein (a) and (b) are optionally furthersubstituted with one or more R¹¹⁷; R¹⁰⁵ is selected from: (a) R¹¹⁴, (b)—OR¹¹⁴, (c) —NR¹¹⁴R¹¹⁴, (d) —O—C₁₋₆ alkyl-R¹¹⁵, (e) —C(O)—R¹¹⁴, (f)—C(O)—C₁₋₆ alkyl-R¹¹⁵, (g) —OC(O)—R¹¹⁴, (h) —OC(O)—C₁₋₆ alkyl-R¹¹⁵, (i)—OC(O)O—R¹¹⁴, (j) —OC(O)O—C₁₋₆ alkyl-R¹¹⁵, (k) —OC(O)NR¹¹⁴R¹¹⁴, (l)—OC(O)NR¹¹⁴—C₁₋₆ alkyl-R¹¹⁵, (m) —C(O)—C₂₋₆ alkenyl-R¹¹⁵, and (n)—C(O)—C₂₋₆ alkynyl-R¹¹⁵;

alternatively, R¹⁰⁴ and R¹⁰⁵, taken together with the atoms to whichthey are bonded, form

wherein Q is CH or N, and R¹²⁶ is —OR¹¹⁴, —NR¹¹⁴ or R¹¹⁴;

alternatively, R¹⁰⁴ and R¹⁰⁵, taken together with the atoms to whichthey are bonded, form:

wherein

-   -   i) R¹⁰¹ is as defined above;    -   ii) alternately, R¹⁰¹ and R¹⁰⁹ can be taken together with the        carbon to which they are attached to form a carbonyl group;    -   iii) alternately, R¹⁰¹ and R¹⁰⁹ can be taken together to form        the group —O(CR¹¹⁶R¹¹⁶)_(u)O—;

alternatively, R¹⁰⁴ and R¹⁰⁵, taken together with the atoms to whichthey are bonded, form:

wherein in the preceding structure the dotted line indicates an optionaldouble bond,

-   -   i) R¹³⁰ is —OH, or R¹¹⁴,    -   ii) R¹³¹ is —OH, or R¹¹⁴,    -   iii) alternately, R¹³⁰ and R¹³¹ together with the carbons to        which they are attached form a 3-7 membered saturated,        unsaturated or aromatic carbocyclic or heterocyclic ring which        can optionally be substituted with one or more R¹¹⁴ groups;    -   iv) alternatively, R¹³⁰ and the carbon to which it is attached        or R¹³¹ and the carbon to which it is attached are each        independently —C(═O)—

alternatively, R¹⁰⁵, R¹³² and M, taken together with the atoms to whichthey are attached, form:

R¹⁰⁶ is selected from:

-   -   (a) —OR¹¹⁴, (b) —C₁₋₆ alkoxy-R¹¹⁵, (c) —C(O)R¹¹⁴, (d)        —OC(O)R¹¹⁴, (e) —OC(O)OR¹¹⁴, (f) —OC(O)NR¹¹⁴R¹¹⁴, and (g)        —NR¹¹⁴R¹¹⁴,

alternatively, R¹⁰⁵ and R¹⁰⁶ taken together with the atoms to which theyare attached form a 5-membered ring by attachment to each other througha chemical moiety selected from:

-   -   (a) —OC(R¹¹⁵)₂O—, (b) —OC(O)O—, (c) —OC(O)NR¹¹⁴—, (d)        —NR¹¹⁴C(O)O—, (e) —OC(O)NOR¹¹⁴—, (f) —NOR¹¹⁴—C(O)O—, (g)        —OC(O)NNR¹¹⁴R¹¹⁴—, (h) —NNR¹¹⁴R¹¹⁴—C(O)O—, (i)        —OC(O)C(R¹¹⁵)—, (j) —C(R¹¹⁵)C(O)O—, (k) —OC(S)O—, (l)        —OC((S)NR¹¹⁴—, (m) —NR¹¹⁴C(S)O—, (n) —OC(S)NOR¹¹⁴, (o)        —NOR¹¹⁴—C(S)O—, (p) —OC(S)NNR¹¹⁴R¹¹⁴—, (q)        —NNR¹¹⁴R¹¹⁴R—C(S)O—, (r) —OC(S)C(R¹¹⁵)₂—, and (s)        C(R¹¹⁵)₂C(S)O—;

alternatively, R¹⁰⁵, R¹⁰⁶, and R¹³³ taken together with the atoms towhich they are attached form:

alternatively, M, R¹⁰⁵, and R¹⁰⁶ taken together with the atoms to whichthey are attached form:

wherein in the preceding structure the dotted line Indicates an optionaldouble bond.

wherein J¹ and J² are selected from hydrogen, Cl, F, Br, I, OH, —C₁₋₆alkyl, and —O(C₁₋₆alkyl) or are taken together to form ═O, ═S, ═NR¹¹⁴,═NOR¹¹⁴, NR¹¹⁴, or ═N—NR¹¹⁴,R¹¹⁴;

alternatively, M and R¹⁰⁴ taken together with the atoms to which theyare attached form:

wherein U is selected from (a) —(C₄-alkyl)- and (b) —(C₄-alkenyl)-,wherein (a) and (b) are optionally further substituted with one or moreR¹¹⁷;

alternatively, M and R¹⁰⁵ are taken together with the atoms to whichthey are attached to form:

R¹⁰⁷ is selected from

-   -   (a) H, (b) —C₁₋₄ alkyl, (c) —C₂₋₄ alkenyl, which can be further        substituted with C₁₋₁₂ alkyl or one or more halogens, (d) —C₂₋₄        alkynyl, which can be further substituted with C₁₋₁₂ alkyl or        one or more halogens, (e) aryl or heteroaryl, which can be        further substituted with C₁₋₁₂ alkyl or one or more        halogens, (f) —C(O)H, (g) —COOH, (h) —CN, (i) —COOR¹¹⁴, j)        —C(O)NR¹¹⁴R¹¹⁴, (k) —C(O)R¹¹⁴, and (l) —C(O)SR¹¹⁴, wherein (b)        is further substituted with one or more substituents selected        from (aa) —OR¹¹⁴, (bb) halogen, (cc) —SR¹¹⁴, (dd) C₁₋₁₂ alkyl,        which can be further substituted with halogen, hydroxyl, C₁₋₆        alkoxy, or amino, (ee) —OR¹¹⁴, (ff) —SR¹¹⁴, (gg) —NR¹¹⁴R¹¹⁴,        (hh) —CN, (ii) —NO₂, (jj) —NC(O)R¹¹⁴, (kk) —COOR¹¹⁴, (ll)        —N₃, (mm) ═N—O—R¹¹⁴, (nn) ═NR¹¹⁴, (oo) ═N—NR¹¹⁴R¹¹⁴, (pp)        ═N—NH—C(O)R¹¹⁴, and (qq) ═N—NH—C(O)NR¹¹⁴R¹¹⁴;

alternatively R¹⁰⁶ and R¹⁰⁷ are taken together with the atom to whichthey are attached to form an epoxide, a carbonyl, an olefin, or asubstituted olefin, or a C₃-C₇ carbocyclic, carbonate, or carbamate,wherein the nitrogen of said carbamate can be further substituted with aC₁-C₆ alkyl;

R¹⁰⁸ is selected from:

-   -   (a) C₁₋₆ alkyl, (b) C₂₋₄ alkenyl, and (c) C₂₋₆ alkynyl,        -   wherein any of (a)-(c) optionally is substituted with one or            more R¹¹⁴ groups;    -   R¹¹¹ is selected from H and —C(O)R¹¹⁴;    -   R¹¹² is selected from H, OH, and OR¹¹⁴;    -   R¹¹³ is selected from:        -   (a) H, (b) R¹¹⁴, (c) —C₁₋₆ alkyl-K—R¹¹⁴, (d) —C₂₋₆            alkenyl-K—R¹¹⁴, and        -   (e) —C₂₋₆ alkynyl-K—R¹¹⁴,            -   wherein any of (c)-(e) optionally is substituted with                one or more R¹¹⁵ groups;    -   R¹¹⁴, at each occurrence, independently is selected from:        -   (a) H, (b) C₁₋₆ alkyl, (c) C₂₋₆ alkenyl, (d) C₂₋₆            alkynyl, (e) C₆₋₁₀ saturated, unsaturated, or aromatic            carbocycle, (f) 3-12 membered saturated, unsaturated, or            aromatic heterocycle containing one or more heteroatoms            selected from nitrogen, oxygen, and sulfur, (g) —C(O)—C₁₋₆            alkyl, (h) —C(O)—C₂₋₄ alkenyl, (i) —C(O)—C₂₋₆ alkynyl, (j)            —C(O)—C₆₋₁₀ saturated, unsaturated, or aromatic            carbocycle, (k) —C(O)-3-12 membered saturated, unsaturated,            or aromatic heterocycle containing one or more heteroatoms            selected from nitrogen, oxygen, and sulfur, (l) —C(O)O—C₁₋₆            alkyl, (m) —C(O)O—C₂₋₆ alkenyl, (n) —C(O)O—C₂₋₆ alkynyl, (o)            —C(O)O—C₆₋₁₀ saturated, unsaturated, or aromatic            carbocycle, (p) —C(O)O-3-12 membered saturated, unsaturated,            or aromatic heterocycle containing one or more heteroatoms            selected from nitrogen, oxygen, and sulfur, (q)            —C(O)NR¹¹⁶R¹¹⁶, (r) —NR¹¹⁶CO—C2-6 alkyl, (s) —NR¹¹⁶CO—C₆₋₁₀            saturated, unsaturated, or aromatic carbocycle, and (t)            —NR¹¹⁶C(O)-3-12 membered saturated, unsaturated, or aromatic            heterocycle containing one or more heteroatoms selected from            nitrogen, oxygen, and sulfur,            -   wherein any of (b)-(t) optionally is substituted with                one or more R¹¹⁵ groups, wherein one or more                non-terminal carbon moieties of any of (b)-(d)                optionally is replaced with oxygen, S(O)_(p), or                —NR^(It)q

alternatively, NR¹¹⁴R¹¹⁴ forms a 3-7 membered saturated, unsaturated oraromatic ring including the nitrogen atom to which the R¹¹⁴ groups arebonded and optionally one or more moieties selected from O, S(O)_(p), N,and NR¹¹⁸;

R¹¹⁵ is selected from:

-   -   (a) R¹¹⁷, (b) C₁₋₈ alkyl, (c) C₂₋₈ alkenyl, (d) C₂₋₈        alkynyl, (e) C₃₋₁₂ saturated, unsaturated, or aromatic        carbocycle, (f) 3-12 membered saturated, unsaturated, or        aromatic heterocycle containing one or more heteroatoms selected        from nitrogen, oxygen, and sulfur,        -   wherein any of (b)-(f) optionally is substituted with one or            more R¹¹⁷ groups;

R¹¹⁶, at each occurrence, independently is selected from:

-   -   (a) H, (b) C₁₋₆ alkyl, (c) C₂₋₆ alkenyl, (d) C₂₋₆ alkynyl, (a)        C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, and (f)        3-10 membered saturated, unsaturated, or aromatic heterocycle        containing one or more heteroatoms selected from nitrogen,        oxygen, and sulfur,        -   wherein one or more non-terminal carbon moieties of any of            (b)-(d) optionally is replaced with oxygen, S(O)_(p), or            —NR¹¹⁴, wherein any of (b)-(f) optionally is substituted            with one or more moieties selected from:            -   (aa) carbonyl, (bb) formyl, (cc) F, (dd) Cl, (ee) Br,                (ff) I, (gg) CN, (hh) N₃, (ii) NO₂, (j) OR¹¹⁸, (kk)                —S(O)_(PR) ¹¹⁸, (ll) —C(O)R¹¹⁸, (mm) —C(O)OR¹¹⁸, (nn)                —OC(O)R¹¹⁸, (oo) —C(O)NR¹¹⁸R¹¹⁸, (pp) —OC(O)NR¹¹⁸R¹¹⁸,                (qq) —C(—NR¹¹⁸)R¹¹⁸, (rr) —C(R¹¹⁴)(R¹¹⁸)OR¹¹⁸, (ss)                —C(R¹¹⁸)₂OC(O)R¹¹⁸, (tt)                —C(R¹¹⁸)(OR¹¹⁸)(CH₂)_(r)NR¹¹⁸R¹¹⁸, (uu) —NR¹¹⁸R¹¹⁸; (vv)                —NR¹¹⁸OR¹¹⁸, (ww) —NR¹¹⁸(O)R¹¹⁸, (xx) —NR¹¹⁸C(O)OR¹¹⁸,                (yy) —NR¹¹⁸C(O)NR¹¹⁸R¹¹⁸, (zz) —NR¹¹⁸S(O)_(r)R¹¹⁸, (ab)                —C(OR¹¹⁸)(OR¹¹⁸)R¹¹⁸, (ac) —C(R¹¹⁸)₂NR¹¹⁸R¹¹⁸, (ad)                —NR¹¹⁸, (ae) —C(S)NR¹¹⁸R¹¹⁸, (af) —NR¹¹⁸C(S)R¹¹⁸, (ag)                —OC(S)NR¹¹⁸R¹¹⁸, (ah) —NR¹¹⁸C(S)OR¹¹⁸, (ai)                —NR¹¹⁸C(S)NR¹¹⁸R¹¹⁸, (aj) —SC(O)R¹¹⁸, (ak) C₁₋₆ alkyl,                (al) C₂₋₆ alkenyl, (am) C₂₋₈ alkynyl, (an) C₁₋₈ alkoxy,                (ao) C₁₋₈ alkylthio, (ap) C₁₋₈ acyl, (aq) saturated,                unsaturated, or aromatic C₃₋₁₀ carbocycle, and (ar)                saturated, unsaturated, or aromatic 3-10 membered                heterocycle containing one or more heteroatoms selected                from nitrogen, oxygen, and sulfur,

alternatively, NR¹¹⁶R¹¹⁶ forms a 3-10 membered saturated, unsaturated oraromatic ring including the nitrogen atom to which the R¹¹⁶ groups areattached and optionally one or more moieties selected from O, S(O)_(p),N, and NR¹¹⁸;

alternatively, CR¹¹⁶R¹¹⁶ forms a carbonyl group;

R¹¹⁷, at each occurrence, is selected from:

-   -   (a) H, (b) ═O, (c) F, (d) Cl, (c) Br, (t) I, (g)        (CR¹¹⁶R¹¹⁶)_(r)CF₃, (h) (CR¹¹⁶R¹¹⁶)_(r)CN, (i)        (CR¹¹⁶R¹¹⁶)_(r)NO₂, (j)        (CR¹¹⁶R¹¹⁶)_(r)NRR¹¹⁶(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (k)        (CR¹¹⁶R¹¹⁶)_(r)OR¹¹⁹, (l)        (CR¹¹⁶R¹¹⁶)_(r)S(O)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (m)        (CR¹¹⁶R¹¹⁶)_(r)C(O)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁶, (n)        (CR¹¹⁶R¹¹⁶)_(r)OC(O)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (o)        (CR¹¹⁶R¹¹⁶)_(r)SC(O)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (p)        (CR¹¹⁶R¹¹⁶)_(r)C(O)O(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (q)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶C(O)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (r)        (CR¹¹⁶R¹¹⁶)_(r)C(O)NR¹¹⁶(CR¹¹⁶R¹¹⁶)_(r)R¹¹⁴, (s)        (CR¹¹⁶R¹¹⁶)_(r)C(═NRR¹¹⁶)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (t)        (CR¹¹⁶R¹¹⁶)_(r)C(═NNR¹¹⁶R¹¹⁶)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (u)        (CR¹¹⁶R¹¹⁶)_(r)C(NNR¹¹⁶C(O)R¹¹⁶)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (v)        (CR¹¹⁶R¹¹⁶)_(r)C(═NOR¹¹⁹)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (x)        (CR¹¹⁶R¹¹⁶)_(r)OC(O)NR¹¹⁶(CR¹¹⁶R¹¹⁶)_(r)R¹¹⁹, (y)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶C(O)NR¹¹⁶(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (z)        (CR¹¹⁶R¹¹⁶)_(t)NR¹¹⁶S(O)_(p)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (aa)        (CR¹¹⁶R¹¹⁶)_(r)S(O)_(p)NR¹¹⁶(CR¹¹⁶R¹¹⁶)_(r)R¹¹⁹, (bb)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶S(O)_(p)NR¹¹⁶(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (cc)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶R¹¹⁶, (dd) C₁₋₆ alkyl, (e) C₂₋₆ alkenyl,        (ff) C₂₋₆ alkynyl, (gg) (CR¹¹⁶R¹¹⁶)_(r)-3-10 saturated,        unsaturated, or aromatic carbocycle, and (hh)        (CR¹¹⁶R¹¹⁶)_(r)-3-10 membered saturated, unsaturated, or        aromatic heterocycle containing one or more heteroatoms selected        from nitrogen, oxygen, and sulfur,        -   wherein any of (dd)-(hh) optionally is substituted with one            or more R¹¹⁹ groups;

alternatively, two R¹¹⁷ groups can form —O(CH₂)_(u)O—;

R¹¹⁸ is selected from:

-   -   (a) H, (b) C₁₋₆ alkyl, (c) C₂₋₆ alkenyl, (d) C₂₋₆ alkynyl, (e)        C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, (f) 3-10        membered saturated, unsaturated, or aromatic heterocycle        containing one or more heteroatoms selected from nitrogen,        oxygen, and sulfur, (g) —C(O)—C₁₋₆ alkyl, (h) —C(O)—C₁₋₆        alkenyl, (g) —C(O)—C₁₋₆ alkynyl, (i) —C(O)—C₃₋₁₀ saturated,        unsaturated, or aromatic carbocycle, and (j) —C(O)-3-10 membered        saturated, unsaturated, or aromatic heterocycle containing one        or more heteroatoms selected from nitrogen, oxygen, and sulfur,        -   wherein any of (b)-(j) optionally is substituted with one or            more moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd)            Br, (ee) I, (ff) CN, (gg) NO₂, (hh) OH, (ii) NH₂, (jj)            NH(C₁₋₆ alky (l), (kk) N(C₁₋₆ alky (l)₂, (ll) C₁₋₆            alkoxy, (mm) aryl, (nn) substituted aryl, (oo) heteroaryl,            (pp) substituted heteroaryl, and (qq) C₁₋₆ alkyl, optionally            substituted with one or more moieties selected from aryl,            substituted aryl, heteroaryl, substituted heteroaryl. F, Cl,            Br, I, CN, NO₂, and OH;

R¹¹⁹, at each occurrence, independently is selected from:

-   -   (a) R¹²⁰, (b) C₁₋₆ alkyl, (c) C₂₋₆ alkenyl, (d) C₂₋₆        alkynyl, (e) C₃₋₁₀ saturated, unsaturated, or aromatic        carbocycle, and (f) 3-10 membered saturated, unsaturated, or        aromatic heterocycle containing one or more heteroatoms selected        from nitrogen, oxygen, and sulfur,        -   wherein any of (b)-(f) optionally is substituted with one or            more R¹¹⁹ groups;

R¹²⁰, at each occurrence, independently is selected from:

-   -   (a) H, (b) ═O, (c) F, (d) Cl, (e) Br, (f) I, (g)        (CR¹¹⁶R¹¹⁶)_(r)CF₃, (h) (CR¹¹⁶R¹¹⁶)_(r)CN, (i)        (CR¹¹⁶R¹¹⁶)_(r)NO₂, (j) (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶R¹¹⁶, (k)        (CR¹¹⁶R¹¹⁶)_(r)OR¹¹⁴, (l) (CR¹¹⁶R¹¹⁶)_(r)S(O)_(p)R¹¹⁶, (m)        (CR¹¹⁶R¹¹⁶)_(r)C(O)R¹¹⁶, (n) (CR¹¹⁶R¹¹⁶)_(r)C(O)OR¹¹⁶, (o)        (CR¹¹⁶R¹¹⁶)_(r)OC(O)R¹¹⁶, (p) (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶C(O)R¹¹⁶, (q)        (CR¹¹⁶R¹¹⁶)_(r)C(O)NR¹¹⁶R¹¹⁶, (r)        (CR¹¹⁶R¹¹⁶)_(r)C(═NR¹¹⁶)R¹¹⁶, (s)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶C(O)NR¹¹⁶R¹¹⁶, (t)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶S(O)_(p)R¹¹⁶, (u)        (CR¹¹⁶R¹¹⁶)_(r)S(O)_(p)NR¹¹⁶R¹¹⁶, (v)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶S(O)_(p)NR¹¹⁶R¹¹⁶, (w) C₁₋₆ alkyl, (x) C₂₋₆        alkenyl, (y) C₂₋₆ alkynyl, (z) (CR¹¹⁶R¹¹⁶)_(r)—C₃₋₁₀ saturated,        unsaturated, or aromatic carbocycle, and (aa)        (CR¹¹⁶R¹¹⁶)_(r)-3-10 membered saturated, unsaturated, or        aromatic heterocycle containing one or more heteroatoms selected        from nitrogen, oxygen, and sulfur,        -   wherein any of (w)-(aa) optionally is substituted with one            or more moieties selected from R¹¹⁶, F, Cl, Br, I, CN, NO₂,            —OR¹¹⁶, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, C₁₋₆ alkoxy,            C₁₋₆ alkylthio, and C₁₋₆ acyl;

R¹²¹, at each occurrence, independently is selected from:

-   -   (a) H, (b) —OR¹¹⁸, (o) —O—C₁₋₆alkyl-OC(O)R¹¹⁸, (d) —O—C₁₋₆        alkyl-OC(O)OR¹¹⁸, (e) —O—C₁₋₆ alkyl-OC(O)NR¹¹⁸R¹¹⁸, (f) —O—C₁₋₆        alkyl-C(O)NR¹¹⁸R¹¹⁸, (g) —C₁₋₆ alkyl-NR¹¹⁸C(O)R¹¹⁸, (h) —O—C₁₋₆        alkyl-NR¹¹⁸C(O)OR¹¹⁸, (i) —O—C₁₋₆ alkyl-NR¹¹⁸C(O)NR¹¹⁸R¹¹⁸, (j)        —O—C₁₋₆ alkyl-NR¹¹⁸C(═N(H)NR¹¹⁸R¹¹⁸, (k) —O—C₁₋₆        alkyl-S(O)_(p)R¹¹⁸, (l) —O—C₂₋₆ alkenyl-OC(O)R¹¹⁸(m) —O—C₁₋₆        alkenyl-OC(O)OR¹¹⁸, (n) —O—C₂₋₆ alkenyl-OC(O)NR¹¹⁸R¹¹⁸, (o)        —O—C₂₋₆ alkenyl-C(O)NR¹¹⁸R¹¹⁸, (p) —O—C₂₋₆        alkenyl-NR¹¹⁸C(O)R¹¹⁸, (q) —O—C₂₋₆ alkenyl-NR¹¹⁸C(O)OR¹¹⁸, (r)        —O—C₂₋₆ alkenyl-NR¹¹⁸C(O)NR¹¹⁸R¹¹⁸, (s) —C₂₋₆        alkenyl-NR¹¹⁸C(═N(H)NR¹¹⁸R¹¹⁸, (t) —O—C₂₋₆ alkenyl-S(O)_(p)R¹¹⁸,    -   (u) —O—C₂₋₆ alkynyl-OC(O)R¹¹⁸, (v) —O—C₂₋₆        alkynyl-OC(O)OR¹¹⁸, (w) —O—C₂₋₆ alkynyl-OC(O)NR¹¹⁸R¹¹⁸, (x)        —O—C₂₋₆ alkynyl-C(O)NR¹¹⁸R¹¹⁸, (y) —O—C₂₋₆        alkynyl-NR¹¹⁸C(O)R¹¹⁸, (z) —O—C₂₋₆ alkynyl-NR¹¹⁸C(O)OR¹¹⁸, (aa)        —C₂₋₆ alkynyl-NR¹¹⁸C(O)NR¹¹⁸R¹¹⁸, (bb) —C₂₋₆        alkynyl-NR¹¹⁸C(═N(H)NR¹¹⁸R¹¹⁸, (cc) —O—C₂₋₆ alkynyl-S(O)R¹¹⁸;        and (dd) —NR¹¹⁸R¹¹⁸;

alternatively, two R¹²¹ groups taken together form ═O, —NOR¹¹⁸, or═NNR¹¹⁸R¹¹⁸;

R¹²² is R¹³⁵;

R¹²³ is selected from:

-   -   (a) R¹¹⁶, (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g) NO₂, and (h)        —OR¹¹⁴;

alternatively, R¹²² and R¹²³ taken together are —O(CH₂)_(u)O—;

R¹²⁴, at each occurrence, independently is selected from:

-   -   (a) H, (b) F, (c) Cl, (d) Br, (e) I, (i) CN, (g) —OR¹¹⁴, (h)        —NO₂, (i) —NR¹¹⁴R¹¹⁴, (j) C₁₋₆ alkyl, (k) C₁₋₆ acyl, and (l)        C₁₋₆ alkoxy;

R¹²⁵ is selected from:

-   -   (a) C₁₋₆ alkyl, (b) C₂₋₆ alkenyl, (c) C₂₋₆ alkynyl, (d) C₁₋₆        acyl, (e) C₁₋₆ alkoxy, (f) C₁₋₆ alkylthio, (g) saturated,        unsaturated, or aromatic C₅₋₁₀ carbocycle, (b) saturated,        unsaturated, or aromatic 5-10 membered heterocycle containing        one or more heteroatoms selected from nitrogen, oxygen, and        sulfur, (i) —O—C₁₋₆ alkyl-saturated, unsaturated, or aromatic        5-10 membered heterocycle containing one or more heteroatoms        selected from nitrogen, oxygen, and sulfur, (j) —NR¹¹⁴—C₁₋₆        alkyl-saturated, unsaturated, or aromatic 5-10 membered        heterocycle containing one or more heteroatoms selected from        nitrogen, oxygen, and sulfur, (k) saturated, unsaturated, or        aromatic 10-membered bicyclic ring system optionally containing        one or more heteroatoms selected from nitrogen, oxygen, and        sulfur, (l) saturated, unsaturated, or aromatic 13-membered        tricyclic ring system optionally containing one or more        heteroatoms selected from nitrogen, oxygen, and sulfur, (m)        —OR¹¹⁴,    -   (n) —NR¹¹⁴R¹¹⁸, (o) —S(O)_(p)R¹¹⁴, and (p) —R¹²⁴,        -   wherein any of (a)-(l) optionally is substituted with one or            more R¹¹⁵ groups;

alternatively, R¹²⁵ and one R¹²⁴ group, taken together with the atoms towhich they are bonded, form a 5-7 membered saturated or unsaturatedcarbocycle, optionally substituted with one or more R¹¹⁵ groups; or a5-7 membered saturated or unsaturated heterocycle containing one or moreatoms selected from nitrogen, oxygen, and sulfur, and optionallysubstituted with one or more R¹¹⁵ groups;

R¹²⁶ at each occurrence, independently is selected from:

-   -   (a) hydrogen, (b) an electron-withdrawing group, (c) aryl, (d)        substituted aryl, (e) heteroaryl, (f) substituted heteroaryl,        and (g) C₁₋₆ alkyl, optionally substituted with one or more R¹¹⁵        groups;

alternatively, any R¹²⁶ and any R¹²³, taken together with the atoms towhich they are bonded, form a 5-7 membered saturated or unsaturatedcarbocycle, optionally substituted with one or more R¹¹⁵ groups; or a5-7 membered saturated or unsaturated heterocycle containing one or moreatoms selected from nitrogen, oxygen, and sulfur, and optionallysubstituted with one or more R¹¹⁵ groups;

-   -   R¹⁰⁹ is H or F;    -   R¹²⁷ is R¹¹⁴, a monosaccharide or disaccharide (including amino        sugars and halo sugar(s),        —(CH₂)_(n)—(O—CH₂CH₂—)_(m)—O(CH₂)_(p)CH₃ or        —(CH₂)_(n)—(O—CH₂CH₂—)_(m)—OH,    -   R¹²⁸ is R¹¹⁴,    -   R¹²⁹ is R¹¹⁴, and    -   R¹¹⁰ is R¹¹⁴.        Alternatively, R¹⁰⁰ and R¹¹⁰ taken together with the carbons to        which they are attached form:

Alternately, R¹²⁸ and R¹²⁹ together with the carbons to which they areattached form a 3-6 membered saturated, unsaturated or aromaticcarbocyclic or heterocyclic ring which can optionally be substitutedwith one or more R¹¹⁴ groups;

-   -   R¹³², R¹³³, and R¹³⁴ are each independently selected from (a)        H, (b) F, (o) Cl, (d) Br, (e) —OR¹¹⁴, (f) —SR¹¹⁴, (g)        —NR¹¹⁴R¹¹⁴, and (h) C₁₋₆ alkyl, wherein (h) optionally is        substituted with one or more R¹¹⁵ groups;    -   alternatively, R¹³² and R¹³³ are taken together to form a        carbon-carbon double;    -   alternatively, R¹³³ and R¹³⁴ are taken together to form ═O, ═S,        ═NOR¹³⁴, ═NR¹¹⁴, and ═N—NR¹¹⁴,R¹¹⁴;    -   alternatively, R¹⁰⁵ and R¹³⁴ are taken together with the carbons        to which they are attached to form a 3-membered ring, said ring        optionally containing an oxygen or nitrogen atom, and said ring        being optionally substituted with one or more R¹¹⁴ groups;    -   alternatively when M is a carbon moiety, R¹³⁴ and M are taken        together to form a carbon-carbon double bond;    -   k, at each occurrence is 0, 1, or 2;    -   m, at each occurrence is 0, 1, 2, 3, 4, or 5;    -   n, at each occurrence is 1, 2, or 3.

In the compounds described above, T is, for example, a macrolideselected from:

or an N-oxide pharmaceutically acceptable salt, eater, or prodrugthereof, wherein M, R¹⁰⁰, R¹⁰¹, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁸, R¹⁰⁹, R¹¹⁰,and R¹²⁰ are as described above.

In the compounds described above, T is, for example, a macrolideselected from:

or an N-oxide pharmaceutically acceptable salt, eater, or prodrugthereof, wherein M, R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰⁴, R¹⁰⁹, R¹¹⁴, R¹²⁶ and R¹²⁷are as described above.

In the compounds described above, T is, for example, a macrolideselected from:

or an N-oxide pharmaceutically acceptable salt, ester, or prodrugthereof, wherein M, R¹, R², R¹⁰⁴, R¹¹⁴, R¹⁰⁹ and R¹²⁷ are as describedabove.

In the compound described above, T is, for example, a macrolide selectedfrom T1 through T33:

As is seen from the foregoing, the macrolide component of the compoundsof the present invention can comprise a wide range of structures.Examples of such macrolide components and their syntheses are providedin the following documents, all of which are incorporated by referencein their entirety: PCT application No. WO 2005/118610, published Dec.15, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO2005/085266, published Sep. 15, 2005, to Rib-X Pharmaceuticals, Inc.;PCT application No. WO 2005/049632, published Jun. 2, 2005, to Rib-XPharmaceuticals, Inc.; PCT application No. WO 2005/042554, published May12, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO2004/078770, published Sep. 16, 2004, to Rib-X Pharmaceuticals, Inc.;PCT application No. WO 2004/029066, published Apr. 8, 2004, to Rib-XPharmaceuticals, Inc.; U.S. Patent No.; U.S. Pat. No. 6,992,069, to Guet al., issued Jan. 31, 2006; U.S. Pat. No. 6,953,782, to Phan et al.,issued Oct. 1, 2005; U.S. Pat. No. 6,939,861, to Ashley et al., issuedSep. 6, 2005; U.S. Pat. No. 6,927,057, to Khoula et al., issued Aug. 9,2005; U.S. Pat. No. 6,794,366, to Chu et al., issued Sep. 21, 2004; U.S.Pat. No. 6,762,168, to Chu, issued Jul. 13, 2004; U.S. Pat. No.6,756,359, to Chu et al, issued Jun. 29, 2994; U.S. Pat. No. 6,750,205,to Ashley et al, issued Jun. 15, 2004; U.S. Pat. No. 6,740,642, toAngehran et al., issued May 25, 2004; U.S. Pat. No. 6,727,352, to Chenget al., issued Apr. 27, 2004; U.S. Patent Application Publication No. US2006/0154881, to Or et al., published Jul. 13, 2006; U.S.

Patent Application Publication No. US 2006/0142215, to Tang et al.,published Jun. 29, 2006; U.S. Patent Application Publication No. US2006/0142214, to Or et al, published Jun. 29, 2006; U.S. PatentApplication Publication No. US 2006/0122128, to Or et al., publishedJun. 8, 2006; U.S. Patent Application Publication No. US 2006/0069048,to Or et al. published Mar. 30, 2006; U.S. Patent ApplicationPublication No. US 2005/0272672, to Li et al., published Dec. 8, 2005;U.S. Patent Application Publication No US 2005/0009764, to Burger et al,published Jan. 13, 2005; PCT application No. WO 2006/067589, to PfizerProducts Inc., published Jun. 29, 2006; PCT application No. WO2004/096823, to Chiron Corporation, published Nov. 11, 2004; PCTapplication No. WO 2004/096822, to Chiron Corporation, published Nov.11, 2004; PCT application No. WO 2004/080391, to OptimerPharmaceuticals, Inc., published Sep. 23, 2004; PCT application No. WO2004/078771, to Taisho Pharmaceutical Co., Ltd., published Sep. 16,2004; PCT application no. WO 03/061671, to Kosan Biosciences, Inc.published Jul. 31, 2003; and European Patent Document BP 1 256 587 B1,to the Kitasato Institute, granted Mar. 29, 2006.

The invention also provides a compound having the structurecorresponding to any one of the structures listed in Table 1, or apharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

The invention also provides a pharmaceutical composition that containsone or more of the compounds described above and a pharmaceuticallyacceptable carrier.

The invention also provides a method for treating or preventing adisease state in a mammal by administering to a mammal in need thereofan effective amount of one or more of the compounds described above.

The invention also provides a method of treating a microbial infectionin a mammal by administering to the mammal an effective amount of one ormore of the compounds described above.

The invention also provides a method of treating a fungal infection in amammal by administering to the mammal an effective amount of one or mornof the compounds described above.

The invention also provides a method of treating a parasitic disease ina mammal by administering to the mammal an effective amount of one ormore of the compounds described above.

The invention also provides a method of treating a proliferative diseasein a mammal by administering to the mammal an effective amount of one ormore of the compounds described above.

The invention also provides a method of treating a viral infection in amammal by administering to the mammal an effective amount of one or moreof the compounds described above.

The invention also provides a method of treating an inflammatory diseasein a mammal by administering to the mammal an effective amount of one ormore of the compounds described above.

The invention also provides a method of treating a gastrointestinalmotility disorder in a mammal by administering to the mammal aneffective amount of one or more of the compounds described above.

The invention also provides a method of treating or preventing a diseasestate in a mammal caused or mediated by a nonsense or missense mutationby administering to the mammal an effective amount of one or more of thecompounds described above to suppress expression of the nonsense ormissense mutation.

In the methods described herein, the compound or compounds areadministered orally, parentally, or topically.

The invention also provides a method of synthesizing the compoundsdescribed above.

The invention also provides a medical device containing one or more ofthe compounds described above. For example, the device is a stent.

3. SYNTHESIS OF THE COMPOUNDS OF THE INVENTION

The invention provides methods for making the compounds of theinvention. The following schemes depict exemplary chemistries availablefor synthesizing the compounds of the invention.

Scheme 1 illustrates the synthesis of triazole compounds of type 5 and6. Erythromycin can be N-demethylated as described in the art (U.S. Pat.No. 3,725,385; Flynn et al, (1954) J. AM. CHEM. SOC. 76: 3121; Ku at al,(1997) BIOORG. MED. CHEM. LETT. 7: 1203; Stenmark et al, (2000) J. ORG.CHEM. 65: 3875) to afford secondary amine 1. Alkylation of 1 withelectrophiles of type 2 yields alkynes of type 3 containing an alkylchain of appropriate length, generally between one and about four carbonatoms between the nitrogen atom and the alkyne group. Cycloaddition ofazides of type 4 with alkynes 3 generates two regioisomeric triazoleproducts. The reaction can be thermally catalyzed, or a number ofcatalysts could be added to facilitate the reaction (such as, but notlimited to, copper (I) iodide: see Tornoe, C. W. et al. (2002) J. ORG.CHEM. 67: 3057). The major isomer (for steric reasons) is the “anti”isomer 5, a 1,4 disubstituted triazole. The minor component is the “syn”isomer 6, a 1,5 disubstituted triazole.

It is to be understood that other macrolide compounds such as, but notlimited to, azithromycin and clarithromycin, could be N-demethylated andserve as starting materials for the chemistry exemplified in Scheme 1.Target compounds derived from such alternate macrolide precursors are tobe considered within the scope of the present invention.

An alternate approach to compounds similar to compounds 5 and 6 isillustrated by. Scheme 2. Acetylenic alcohols of type 14 can be treatedwith azides 4 to yield intermediate alcohol 15 (along with a minoramount of the regioisomeric triazole). Tosylation of 15 will providetosylates 16 which can serve as alkylating agents for macrolide aminesof type 1 to afford targets S (and its isomer 6), (It will beappreciated that other sulfonate derivatives or halides could be formedfrom intermediate alcohol 15, and these would be useful as electrophilesfor the alkylation of macrolide amines such as 1 to afford compounds ofthe invention.)

Other starting materials for the synthesis of compounds of the presentinvention are readily synthesizable. For example, des-methyl macrolideamines 22 and 23 can be prepared from azithromycin and clarithromycinrespectively, using the same procedure for the synthesis of 1 fromerythxomycin. Ketolide derivatives (C-3 keto compounds synthesized frommacrolides) of the present invention can be prepared by chemistry suchas that shown in Scheme 5. Clarithromycin-derived amine 23 is alkylatedwith tosylate 24 to afford alkyne 25. The cladinose sugar at C-3 ishydrolyzed to afford the C-3 hydroxy intermediate 26, which is thenselectively acetylated on the hydroxyl of the aminosaccharide group toyield 27. Oxidation of 27 yields C-3 keto derivative 28 which is thendeacylated to provide alkyne 29. Alkyne 29 can be exposed to thechemistry of Schemes 1 and 3 above to deliver triazole and isoxazolecompounds of the present invention that have C-3 ketoclarithromycin-derived structures. It will be understood that alkylationof 23 with electrophiles of type 7, and then exposure of the productnitrites to the chemistry shown in Schemes 5 and 2, will yieldtetrazoles that have C-3 keto clarithromycin-derived structures.Additionally, C-3 keto azithromycin and erythromycin intermediates couldbe prepared from 1 and 22 using the chemistry of Scheme 3, andsubsequently serve as starting materials for compounds of the presentinvention.

Intermediate azides of type 4 used to make compounds of the presentinvention can be synthesized using the methods exemplified in Schemes 4and 5. Phenols, anilines, and thiophenols of type 30 can undergoMitsunobu etherification processes with α,ω-halo alcohols (such as, butnot limited to, 2-bromoethanol) to generate halides of type 31.Displacement of the halogen with sodium azide yields azides 4a.Alternatively, direct alkylation of intermediates 30 with α,ω-haloalcohols yields alcohols of type 32, which can be converted to halides31 or converted to a sulfonate derivative such as 33, for subsequentazide displacement to afford azides 4a. Arylpropanols of type 34, andpyridylpropanols of type 35, can be converted to azides 4b and 4c viasulfonatos such as 36 and 37. It will be appreciated that pyridylderivatives with alternate substitution patterns (ortho and para), andalternate chain-lengths between the aryl moiety and the aside group canalso be made using chemistry known in the art. It is intended that allsuch isomers and homologues are within the scope of the presentinvention.

Nitrile oxides of type 11 used to make compounds of the presentinvention can be synthesized using the method exemplified in Scheme 6.Substituted arylalkanols of type 32 (or pyridylalkanols) of variouschain length between the aryl moiety and the alcohol group can beoxidized to aldehydes 38. Conversion of the aldehyde to oximes 39 can befollowed by conversion to intermediate nitrile oxides 11 usingchloramine T (or other reagents used in combination with organic aminebases such as N-bromosuccinimide, N-chlorosuccinimide, t-butylhypochlorite, lead tetraacetate etc.). The reaction to form the nitrileoxide can be run in the presence of an appropriate alkyne to trap theunstable intermediates 11 directly, affording a mixture of anti and synisoxazole products.

4. CHARACTERIZATION OF COMPOUNDS OF THE INVENTION

Compounds designed, selected and/or optimized by methods describedabove, once produced, can be characterized using a variety of assaysknown to those skilled in the art to determine whether the compoundshave biological activity. For example, the molecules can becharacterized by conventional assays, including but not limited to thoseassays described below, to determine whether they have a predictedactivity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysisusing such assays. As a result, it can be possible to rapidly screen themolecules described herein for activity, for example, as anti-cancer,anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents. Also,it can be possible to assay how the compounds interact with a ribosomeor ribosomal subunit and/or are effective as modulators (for example,inhibitors) of protein synthesis using techniques known in the art.General methodologies for performing high-throughput screening aredescribed, for example, in Devlin (1998) High Throughput Screening.Marcel Dekker; and U.S. Pat. No. 5,763,263. High-throughput assays canuse one or more different assay techniques including, but not limitedto, those described below.

(1) Surface Binding Studies. A variety of binding assays can be usefulin screening new molecules for their binding activity. One approachincludes surface plasmon resonance (SPR) that can be used to evaluatethe binding properties of molecules of interest with respect to aribosome, ribosomal subunit or a fragment thereof.

SPR methodologies measure the interaction between two or moremacromolecules in real-time through the generation of aquantum-mechanical surface plasmon. One device, (BIAcore Biosensor® fromPharmacia Biosensor, Piscataway, N.J.) provides a focused beam ofpolychromatic light to the interface between a gold film (provided as adisposable biosensor “chip”) and a buffer compartment that can beregulated by the user. A 100 nm thick “hydrogel” composed ofcarboxylated dextran that provides a matrix for the covalentimmobilization of analytes of interest is attached to the gold film.When the focused light interacts with the free electron cloud of thegold film, plasmon resonance is enhanced. The resulting reflected lightis spectrally depleted in wavelengths that optimally evolved theresonance. By separating the reflected polychromatic light into itscomponent wavelengths (by means of a prism), and determining thefrequencies that are depleted, the BIAcore establishes an opticalinterface which accurately reports the behavior of the generated surfaceplasmon resonance. When designed as above, the plasmon resonance (andthus the depletion spectrum) is sensitive to mass in the evanescentfield (which corresponds roughly to the thickness of the hydrogel). Ifone component of an interacting pair is immobilized to the hydrogel, andthe interacting partner is provided through the buffer compartment, theinteraction between the two components can be measured in real timebased on the accumulation of mass in the evanescent field and itscorresponding effects of the plasmon resonance as measured by thedepletion spectrum. This system permits rapid and sensitive real-timemeasurement of the molecular interactions without the need to labeleither component.

(2) Fluorescence Polarization. Fluorescence polarization (FP) is ameasurement technique that can readily be applied to protein-protein,protein-ligand, or RNA-ligand interactions in order to derive IC₅₀s andKds of the association reaction between two molecules. In this techniqueone of the molecules of interest is conjugated with a fluorophore. Thisis generally the smaller molecule in the system (in this case, thecompound of interest). The sample mixture, containing both theligand-probe conjugate and the ribosome, ribosomal subunit or fragmentthereof, is excited with vertically polarized light. Light is absorbedby the probe fluorophores, and re-emitted a short time later. The degreeof polarization of the emitted light is measured. Polarization of theemitted light is dependent on several factors, but most importantly onviscosity of the solution and on the apparent molecular weight of thefluorophore. With proper controls, changes in the degree of polarizationof the emitted light depends only on changes in the apparent molecularweight of the fluorophore, which in-turn depends on whether theprobe-ligand conjugate is free in solution, or is bound to a receptor.Binding assays based on PP have a number of important advantages,including the measurement of IC₅₀s and Kds under true homogenousequilibrium conditions, speed of analysis and amenity to automation, andability to screen in cloudy suspensions and colored solutions.

(3) Protein & Synthesis. It is contemplated that, in addition tocharacterization by the foregoing biochemical assays, the compound ofinterest can also be characterized as a modulator (for example, aninhibitor of protein synthesis) of the functional activity of theribosome or ribosomal subunit.

Furthermore, more specific protein synthesis inhibition assays can beperformed by administering the compound to a whole organism, tissue,organ, organelle, cell, a cellular or subcellular extract, or a purifiedribosome preparation and observing its pharmacological and inhibitoryproperties by determining, for example, its inhibition constant (IC₅₀)for inhibiting protein synthesis. Incorporation of ³H leucine or ³⁵Smethionine, or similar experiments can be performed to investigateprotein synthesis activity. A change in the amount or the rate ofprotein synthesis in the cell in the presence of a molecule of interestindicates that the molecule is a modulator of protein synthesis. Adecrease in the rate or the amount of protein synthesis indicates thatthe molecule is a inhibitor of protein synthesis.

Furthermore, the compounds can be assayed for anti-proliferative oranti-infective properties on a cellular level. For example, where thetarget organism is a microorganism, the activity of compounds ofinterest can be assayed by growing the microorganisms of interest inmedia either containing or lacking the compound. Growth inhibition canbe indicative that the molecule can be acting as a protein synthesisinhibitor. More specifically, the activity of the compounds of interestagainst bacterial pathogens can be demonstrated by the ability of thecompound to inhibit growth of defined strains of human pathogens. Forthis purpose, a panel of bacterial strains can be assembled to include avariety of target pathogenic species, some containing resistancemechanisms that have been characterized. Use of such a panel oforganisms permits the determination of structure-activity relationshipsnot only in regards to potency and spectrum, but also with a view toobviating resistance mechanisms. The assays can be performed inmicrotiter trays according to conventional methodologies as published byThe National Committee for Clinical Laboratory Standards (NCCLS)guidelines (NCCLS. M7-A5-Methods for Dilution AntimicrobialSusceptibility Tests for Bacteria That Grow Aerobically; ApprovedStandard-Fifth Edition. NCCLS Document M100-S12/M7 (ISBN1-56238-394-9)).

5. FORMULATION AND ADMINISTRATION

The compounds of the invention can be useful in the prevention ortreatment of a variety of human or other animal, including mammalian andnon mammalian, disorders, including for example, bacterial infection,fungal infections, viral infections, parasitic diseases, and cancer. Itis contemplated that, once identified, the active molecules of theinvention can be incorporated into any suitable carrier prior to use.The dose of active molecule, mode of administration and use of suitablecarrier will depend upon the intended recipient and target organism. Theformulations, both for veterinary and for human medical use, ofcompounds according to the present invention typically include suchcompounds in association with a pharmaceutically acceptable carrier.

The carrier(s) should be “acceptable” in the sense of being compatiblewith the other ingredients of the formulations and not deleterious tothe recipient Pharmaceutically acceptable carriers, in this regard, areintended to include any and all solvents, dispersion media, coatings,anti-bacterial and anti-fungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances isknown in the art. Except insofar as any conventional media or agent isincompatible with the active compound, use thereof in the compositionsis contemplated. Supplementary active compounds (identified or designedaccording to the invention and/or known in the art) also can beincorporated into the compositions. The formulations can conveniently bepresented in dosage unit form and can be prepared by any of the methodswell known in the art of pharmacy/microbiology. In general, someformulations are prepared by bringing the compound into association witha liquid carrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

A pharmaceutical composition of the invention should be formulated to becompatible with its intended route of administration. Examples of routesof administration include oral or parenteral, for example, intravenous,intradermal, inhalation, transdermal (topical), transmucosal, and rectaladministration. Solutions or suspensions used for parenteral,intradermal, or subcutaneous application can include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetreacotic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. pH can beadjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide.

Useful solutions for oral or parenteral administration can be preparedby any of the methods well known in the pharmaceutical art, described,for example, in Remington's Pharmaceutical Sciences, (Genmaro, A., ed.),Mack Pub., (1990). Formulations for parenteral administration can alsoinclude glycocholate for buccal administration, methoxysalicylate forrectal administration, or citric acid for vaginal administration. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic. Suppositories forrectal administration also can be prepared by mixing the drug with anon-irritating excipient such as cocoa butter, other glycerides, orother compositions which are solid at room temperature and liquid atbody temperatures. Formulations also can include, for example,polyalkylene glycols such as polyethylene glycol, oils of vegetableorigin, and hydrogenated naphthalenes. Formulations for directadministration can include glycerol and other compositions of highviscosity. Other potentially useful parenteral carriers for these drugsinclude ethylene-vinyl acetate copolymer particles, osmotic pumps,implantable infusion systems, and liposomes. Formulations for inhalationadministration can contain as excipients, for example, lactose, or canbe aqueous solutions containing, for example, polyoxyethylene-9-laurylether, glycocholate and deoxycholate, or oily solutions foradministration in the form of nasal drops, or as a gel to be appliedintranasally. Retention enemas also can be used for rectal delivery.

Formulations of the present invention suitable for oral administrationcan be in the form of: discrete units such as capsules, gelatincapsules, sachets, tablets, troches, or lozenges, each containing apredetermined amount of the drug; a powder or granular composition; asolution or a suspension in an aqueous liquid or non-aqueous liquid; oran oil-in-water emulsion or a water-in-oil emulsion. The drug can alsobe administered in the form of a bolus, electuary or paste. A tablet canbe made by compressing or moulding the drug optionally with one or moreaccessory ingredients. Compressed tablets can be prepared bycompressing, in a suitable machine, the drug in a free-flowing form suchas a powder or granules, optionally mixed by a binder, lubricant, inertdiluent, surface active or dispersing agent. Moulded tablets can be madeby moulding, in a suitable machine, a mixture of the powdered drug andsuitable carrier moistened with an inert liquid diluent.

Oral compositions generally include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients. Oral compositions preparedusing a fluid carrier for use as a mouthwash include the compound in thefluid carrier and are applied orally and swished and expectorated orswallowed. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose; a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). Itshould be stable under the conditions of manufacture and storage andshould be preserved against the contaminating action of microorganismssuch as bacteria and fungi. The carrier can be a solvent or dispersionmedium containing, for example, water, ethanol, polyol (for example,glycerol, propylene glycol, and liquid polyethylene glycol), andsuitable mixtures thereof. The proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use ofsurfactants. In many cases, it will be preferable to include isotonicagents, for example, sugars, polyalcohols such as manitol, sorbitol,and/or sodium chloride in the composition. Prolonged absorption of theinjectable compositions can be brought about by including in thecomposition an agent which delays absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfilter sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation include vacuumdrying and freeze-drying which yields a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Formulations suitable for intra-articular administration can be in theform of a sterile aqueous preparation of the drug that can be inmicrocrystalline form, for example, in the form of an aqueousmicrocrystalline suspension. Liposomal formulations or biodegradablepolymer systems can also be used to present the drug for bothintra-articular and ophthalmic administration.

Formulations suitable for topical administration, including eyetreatment, include liquid or semi-liquid preparations such as liniments,lotions, gels, applicants, oil-in-water or water-in-oil emulsions suchas creams, ointments or pastes; or solutions or suspensions such asdrops. Formulations for topical administration to the skin surface canbe prepared by dispersing the drug with a dermatologically acceptablecarrier such as a lotion, cream, ointment or soap. Particularly usefulare carriers capable of forming a film or layer over the skin tolocalize application and inhibit removal. For topical administration tointernal tissue surfaces, the agent can be dispersed in a liquid tissueadhesive or other substance known to enhance adsorption to a tissuesurface. For example, hydroxypropylcellulose or fibrinogen/thrombinsolutions can be used to advantage. Alternatively, tissue-coatingsolutions, such as pectin-containing formulations can be used.

For inhalation treatments, inhalation of powder (self-propelling orspray formulations) dispensed with a spray can, a nebulizer, or anatomizer can be used. Such formulations can be in the form of a finepowder for pulmonary administration from a powder inhalation device orself-propelling powder-dispensing formulations. In the case ofself-propelling solution and spray formulations, the effect can beachieved either by choice of a valve having the desired spraycharacteristics (i.e., being capable of producing a spray having thedesired particle size) or by incorporating the active ingredient as asuspended powder in controlled particle size. For administration byinhalation, the compounds also can be delivered in the form of anaerosol spray from pressured container or dispenser which contains asuitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration also can be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants generally are known in the art, and include, forexample, for transmucosal administration, detergents and bile salts.

Transmucosal administration can be accomplished through the use of nasalsprays or suppositories. For transdermal administration, the activecompounds typically are formulated into ointments, salves, gels, orcreams as generally known in the art.

The active compounds can be prepared with carriers that will protect thecompound against rapid elimination from the body, such as a controlledrelease formulation, including implants and microencapsulated deliverysystems. Biodegradable, biocompatible polymers can be used, such asethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Methods for preparation of suchformulations will be apparent to those skilled in the art. Liposomalsuspensions can also be used as pharmaceutically acceptable carriers.These can be prepared according to methods known to those skilled in theart, for example, as described in U.S. Pat. No. 4,522,811.

Oral or parenteral compositions can be formulated in dosage unit formfor ease of administration and uniformity of dosage. Dosage unit formrefers to physically discrete units suited as unitary dosages for thesubject to be treated; each unit containing a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved, and the limitationsinherent in the art of compounding such an active compound for thetreatment of individuals. Furthermore, administration can be by periodicinjections of a bolus, or can be made more continuous by intravenous,intramuscular or intraperitoneal administration from an externalreservoir (e.g., an intravenous bag).

Where adhesion to a tissue surface is desired the composition caninclude the drug dispersed in a fibrinogen-thrombin composition or otherbioadhesive. The compound then can be painted, sprayed or otherwiseapplied to the desired tissue surface. Alternatively, the drugs can beformulated for parenteral or oral administration to humans or othermammals, for example, in therapeutically effective amounts, e.g.,amounts that provide appropriate concentrations of the drug to targettissue for a time sufficient to induce the desired effect.

Where the active compound is to be used as part of a transplantprocedure, it can be provided to the living tissue or organ to betransplanted prior to removal of tissue or organ from the donor. Thecompound can be provided to the donor host. Alternatively or, inaddition, once removed from the donor, the organ or living tissue can beplaced in a preservation solution containing the active compound. In allcases, the active compound can be administered directly to the desiredtissue, as by injection to the tissue, or it can be providedsystemically, either by oral or parenteral administration, using any ofthe methods and formulations described herein and/or known in the art.Where the drug comprises part of a tissue or organ preservationsolution, any commercially available preservation solution can be usedto advantage. For example, useful solutions known in the art includeCollins solution, Wisconsin solution, Belzer solution, Eurocollinssolution and lactated Ringer's solution.

The compounds of the present invention can be administered directly to atissue locus by applying the compound to a medical device that is placedin contact with the tissue. An example of a medical device is a stent,which contains or is coated with one or more of the compounds of thepresent invention.

For example, an active compound can be applied to a stent at the site ofvascular injury. Stents can be prepared by any of the methods well knownin the pharmaceutical art See, e.g., Fattori, R. and Piva, T., “DrugEluting Stents in Vascular Intervention,” Lancet, 2003, 361, 247-249;Morice, M. C., “A New Era in the Treatment of Coronary Disease?”European Heart Journal, 2003, 24, 209-211; and Toutouzas, K. et al.,“Sirolimus-Eluting Stents: A Review of Experimental and ClinicalFindings,” Z. Kardiol., 2002, 91(3), 49.57. The stent can be fabricatedfrom stainless steel or another bio-compatible metal, or it can be madeof a bio-compatible polymer. The active compound can be linked to thestent surface, embedded and released from polymer materials coated onthe stent, or surrounded by and released through a carrier which coatsor spans the stent. The stent can be used to administer single ormultiple active compounds to tissues adjacent to the stent.

Active compound as identified or designed by the methods describedherein can be administered to individuals to treat disorders(prophylactically or therapeutically). In conjunction with suchtreatment, pharmacogenomics (I.e., the study of the relationship betweenan individual's genotype and that individual's response to a foreigncompound or drug) can be considered. Differences in metabolism oftherapeutics can lead to severe toxicity or therapeutic failure byaltering the relation between dose and blood concentration of thepharmacologically active drug. Thus, a physician or clinician canconsider applying knowledge obtained in relevant pharmacogenomicsstudies in determining whether to administer a drug as well as tailoringthe dosage and/or therapeutic regimen of treatment with the drug.

In therapeutic use for treating, or combating, bacterial infections inmammals, the compounds or pharmaceutical compositions thereof will beadministered orally, parenterally and/or topically at a dosage to obtainand maintain a concentration, that is, an amount, or blood-level ortissue level of active component in the animal undergoing treatmentwhich will be anti-microbially effective. Generally, an effective amountof dosage of active component will be in the range of from about 0.1 toabout 100, more preferably from about 1.0 to about 50 mg/kg of bodyweight/day. The amount administered will also likely depend on suchvariables as the type and extent of disease or indication to be treated,the overall health status of the particular patient, the relativebiological efficacy of the compound delivered, the formulation of thedrug, the presence and types of excipients in the formulation, and theroute of administration. Also, it is to be understood that the initialdosage administered can be increased beyond the above upper level inorder to rapidly achieve the desired blood-level or tissue level, or theinitial dosage can be smaller than the optimum and the daily dosage canbe progressively increased during the course of treatment depending onthe particular situation. If desired, the daily dose can also be dividedinto multiple doses for administration, for example, two to four timesper day.

Various disease states or conditions in humans and other mammals arefound to be caused by or mediated by nonsense or missense mutations.These mutations cause or mediate the disease state or condition byadversely affecting, for example, protein synthesis, folding,trafficking and/or function. Examples of disease states or conditions inwhich an appreciable percentage of the disease or condition is believedto result from nonsense or missense mutations include hemophilia (factorVIII gene), neurofibromatosis (NF1 and NP2 genes), retinitis pigmentosa(human USH2A gene), bullous skin diseases like Epidermolysis bullosapruriginosa (COL7A1 gene), cystic fibrosis (cystic fibrosistransmembrane regulator gene), breast and ovarian cancer (BRCA1 andBRCA2 genes), Duchenne muscular dystrophy (dystrophin gene), coloncancer (mismatch repair genes, predominantly in MLH1 and MSH2), andlysosomal storage disorders such as Neimann-Pick disease (acidsphingomyelinase gene). See Sanders C R, Myers J K. Disease-relatedmisassembly of membrane proteins. Annu Rev Blophys Biomol Struct. 2004;33:25-51; National Center for Biotechnology Information (U.S.) Genes anddisease Bethesda, Md.: NCBI, NLM ID: 101138560; and Raskó, István;Downes, C S Genes in medicine: molecular biology and hunan peneticdisorders 1st ed. London; New York: Chapman & Hall, 1995. NLM ID:9502404. The compounds of the present invention can be used to treat orprevent a disease state in a mammal caused or mediated by such nonsenseor missense mutations by administering to a mammal in need thereof aneffective amount of the present invention to suppress the nonsense ormissense mutation involved in the disease state.

6. EXAMPLES

Nuclear magnetic resonance (NMR) spectra were obtained on a BrukerAvance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300spectrometer. Common reaction solvents were either high performanceliquid chromatography (HPLC) grade or American Chemical Society (ACS)grade, and anhydrous as obtained from the manufacturer unless otherwisenoted. “Chromatography” or “purified by silica gel” refers to flashcolumn chromatography using silica gel (EM Merck, Silica Gel 60, 230-400mesh) unless otherwise noted.

Some of the abbreviations used in the following experimental details ofthe synthesis of the examples are defined below:

hr=hour(s); min=minute(s); mol=mole(s); mmol=millimole(s); M=molar;μM=micromolar; g=gram(s); μg=microgram(s); rt=room temperature:L=liter(s); mL=milliliter(s); Et₂O=diethyl ether; THF=tetrahydrofuran;DMSO=dimethyl sulfoxide; EtOAc=ethyl acetate; Et₃N=triethylamine;i-Pr₂NEt=diisopropylethylamine; CH₂Cl₂=methylene chloride;CHCl₃=chloroform; CDC₃=deuterated chloroform; CCl₄=carbon tetrachloride;MeOH=methanol; CD₃OD=deuterated methanol; BtOH=ethanol;DMF=dimethylformamide; BOC=t-butoxycarbonyl; CBZ=benzyloxycarbonyl;TBS=t-butyldimethyisilyl; TBSCl=t-butyldimethylsilyl chloride;TFA=trifluoroacetic acid; DBU=diazabicycloundecene;TBDPSCl=t-butyldiphenylchlorosilane; Hunig'sBase═N,N-diisopropylethylamine; DMAP=4-dimethylaminopyridine; CuI=copper(I) iodide; MsCl=methanesulfonyl chloride; NaN₃=sodium azide;Na₂SO₄=sodium sulfate; NaHCO₃=sodium bicarbonate; NaOH=sodium hydroxide;MgSO₄=magnesium sulfate; K₂CO₃=potassium carbonate; KOH=potassiumhydroxide; NH₄OH=ammonium hydroxide; NH₄Cl=ammonium chloride;SiO₂=silica; Pd—C=palladium on carbon;Pd(dppf)C₂=dichloro[1,1′-bis(diphenylposphiosphno)ferrocene] palladium(II).

Exemplary compounds synthesized in accordance with the invention arelisted in Table 1. A bolded or dashed bond is shown to indicate aparticular stereochemistry at a chiral center, whereas a wavy bondindicates that the substituent can be in either orientation or that thecompound is a mixture thereof. It should also be known that in theinterest of space, the chemical structures for some compounds have beencondensed, for example the methyl and ethyl group substituents aredesignated with just a carbon backbone representation, and theunsaturated bonds in the triazole rings might not always be visible.

The compounds of the present invention can be prepared, formulated, anddelivered as pharmaceutically acceptable salts, esters, and prodrugs.For convenience, the compounds are generally shown without indicating aparticular salt, ester, or prodrug form.

TABLE 1 Com- pound Structure 101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

201

202

203

204

205

206

207

210

211

212

213

221

222

223

224

225

226

230

231

232

233

234

235

236

237

238

239

240

241

242

243

Tables 2-5, below, contain the following information and are organizedas follows:

the first column (labeled “Compound”) lists the compound numberscorresponding to those of Table 1, above;

the second column (labeled “B”) provides a structural representation foreach of the compounds for the fragment designated as “-A-G” that isattached to the triazole ring, which is attached to a desosamine sugaror other sugar via a connecting group, where the desosamine sugar orother sugar is attached to T, the 14- to 15-membered macrolide ring. “B”corresponds to that portion of the compound indicated to the right ofthe dotted line as shown in the generic structure, immediately below. Itshould be recognized from the synthetic procedures described herein,that the “B” moiety is usually functionalized as an azide, such that theazide after cycloaddition with the appropriate alkyne is incorporatedinto the triazole ring of the final compounds. The remainder of themolecule, is designated as Mac;

the third column (labeled “Mac”) provides a structural representationfor each of the compounds for the macrolide fragment (this includes the“T” 14- to 15-membered macrolide ring, the desosamine or other sugar,the connecting group, and the triazole) that is attached to the “B”fragment, and corresponds to that portion of the compound indicated tothe left of the dotted line as shown in the generic structure,immediately above. The “Mac” fragments are denoted with an abbreviationand these fragments are shown below in Scheme 7;

the fourth column (labeled “Yield”) provides the yield, where available,for the compounds when prepared from cycloaddition of the correspondingazide and alkynyl substituted macrolide compound;

the fifth column (labeled “LCMS”) provides the liquid chromatographymass spectral data, where available, for the compound.

Scheme 7: Macrolide Fragments “Mac” for Tables 2-5, where “B” is asDefined in Tables 2-5 Below.

Example 1—Synthesis of Compounds 101-198

Schemes 100-101 and Table 2 below relate to the synthesis of compounds101-198. Compounds 101-148, 151-160, 162, 164, 165, 183, 184, and191-198 were made via the alkynyl intermediate, 3.

Alkynyl intermediate 3 was made by selective demethylation ofazithromycin 1 to produce 3′-N-desmethylazithromycin 2. This compound 2was selectively alkylated with alkynyl tosylate 11 to produce alkyne 3,respectively. As shown in Scheme 101 alkyne 3 is reacted withcorresponding azides 14 in the presence of copper (I) iodide toselectively afford the triazoles 101-149, 151-160, 162, 164, 165, 183,184, and 191-198.

The compounds 163, 168, 171-182, and 185-190 were made from azidecompound 161. Azide compound 161 was made from amino compound 150, whichin turn was made from nitro compound 147.

The compounds 169 and, 170 were made from azide compound 167. Azidecompound 167 was made from amino compound 166, which in turn was madefrom nitro compound 108.

Synthesis of 3′-N-Desmethylazithromycin 2

Azithromycin 1 (0.80 g, 1.02 mmol) and sodium acetate (NaOAc) (0.712 &8.06 mmol) were dissolved in 80% aqueous MeOH (25 mL). The solution washeated to 50° C. followed by addition of iodine (1₂) (0.272 g, 1.07mmol) in three batches within 3 minutes. The reaction was maintained ata pH between 8-9 by adding 1N sodium hydroxide (NaOH) (1 mL) at 10 minand 45 minute intervals. The solution turned colorless within 45minutes, however, stirring was continued for 2 hours. TLC(CH₂Cl₂/MeOH/NH₄OH 10:1:0.05) after 2 hours showed a single majorproduct (Rf=0.66). The reaction was cooled to room temperature, pouredinto H₂O (75 mL) containing NH₄OH (1.5 mL) and extracted with CHCl₃(3×30 mL). The combined organic layers were washed with H₂O (30 mL)containing NH₄OH (1.5 mL), dried over Na₂SO₄ and the solvent evaporatedto give a white residue. The crude was purified on a silica gel columneluting with CH₂Cl₂/MeOH/NH₄OH 18:1:0.05 to 10:1:0.05 to provide amine 2(0.41 g, 55%).

Synthesis of Alkyne 3

A mixture of 3′-N-desmethylazithromycin 2 and tosylate 11 in Hunig'sbase was stirred. The reaction mixture was diluted to EtOAc and washedwith NaHCO₃(aq) and with brine. The organic layer was dried over K₂CO₃and the solvent was evaporated to give product. The crude product waspurified on silica gel column to give 3 as a white solid.

TABLE 2 Compound B Mac Yield LCMS 101

M2 83% 512.0 (M + 2H)²⁺ 102

M2 24% 505.0 (M + 2H)²⁺ 103

M2 45% 521.5 (M + 2H)²⁺ 104

M2 87% 511.9 (M + 2H)²⁺ 105

M2 80% 530.1 (M + 2H)²⁺ 106

M2 66% 546.6 (M + 2H)²⁺ 107

M2 76% 527.7 (M + 2H)²⁺ 108

M2 74% 505.6 (M + 2H)²⁺ 109

M2 62% 525.1 (M + 2H)²⁺ 110

M2 95% 522.1 (M + 2H)²⁺ 111

M2 27% 533.1 (M + 2H)²⁺ 112

M2 46% 532.4 (M + 2H)²⁺ 113

M2 72% 529.1 (M + 2H)²⁺ 114

M2 78% 536.1 (M + 2H)²⁺ 115

M2 71% 536.1 (M + 2H)²⁺ 116

M2 84% 520.1 (M + 2H)²⁺ 117

M2 77% 514.1 (M + 2H)²⁺ 118

M2 96% 531.1 (M + 2H)²⁺ 119

M2 87% 545.1 (M + 2H)²⁺ 120

M2 86% 594.6 (M + 2H)²⁺ 121

M2 86% 549.1 (M + 2H)²⁺ 122

M2 88% 541.1 (M + 2H)²⁺ 123

M2 81% 533.1 (M + 2H)²⁺ 124

M2 36% 546.1 (M + 2H)²⁺ 125

M2 74% 536.6 (M + 2H)²⁺ 126

M2 77% 1042.7 (M + H)⁺ 127

M2 60% 536.1 (M + 2H)²⁺ 128

M2 50% 533.7 (M + 2H)²⁺ 129

M2 64% 557.2 (M + 2H)²⁺ 130

M2 25% 516.2 (M + 2H)²⁺ 131

M2 37% 515.9 (M + 2H)²⁺ 132

M2 60% 522.1 (M + 2H)²⁺ 133

M2 80% 528.2 (M + 2H)²⁺ 134

M2 — — 135

M2 82% 486.1 (M + 2H)²⁺ 136

M2 88% 533.1 (M + 2H)²⁺ 1064.8 (M + H)⁺ 137

M2 61% 514.6 (M + 2H)²⁺ 1064.8 (M + H)⁺ 138

M2 85% 512.6 (M + 2H)²⁺ 1024 (M + H)⁺ 139

M2 79% 513.6 (M + 2H)²⁺ 140

M2 75% 530 (M + 2H)²⁺ 141

M2 78% 531 (M + 2H)²⁺ 1060.7 (M + H)⁺ 142

M2 56% 514.6 (M + 2H)²⁺ 1064.8 (M + H)⁺ 143

M2 88% 512.6 (M + 2H)²⁺ 1024 (M + H)⁺ 144

M2 94% 513.6 (M + 2H)²⁺ 145

M2 92% 533.1 (M + 2H)²⁺ 146

M2 90% 529.5 (M + 2H)²⁺ 147

M2 81% 504.5 (M + 2H)²⁺ 148

M2 64% 515.6 (M + 2H)²⁺ 1030.0 (M + H)⁺ 149

M2 77% 530.6 (M + 2H)²⁺ 150

M2 — 489.4 (M + 2H)²⁺ 151

M2 94% 520.5 (M + 2H)²⁺ 152

M2 65% 521.0 (M + 2H)²⁺ 153

M2 98% 535.6 (M + 2H)²⁺ 154

M2 70% 528.8 (M + 2H)²⁺ 155

M2 66% 521.6 (M + 2H)²⁺ 156

M2 40% 505.6 (M + 2H)²⁺ 157

M2 82% 536.8 (M + 2H)²⁺ 158

M2A 20% 515.0 (M + 2H)²⁺ 159

M2A 60% 520.3 (M + 2H)²⁺ 160

M2 61% 528.1 (M + 2H)²⁺ 161

M2 — 502.7 (M + 2H)²⁺ 162

M2 40% 539.0 (M + 2H)²⁺ 163

M2 — 593.8 (M + 2H)²⁺ 164

M2 60% 516.6 (M + 2H)²⁺ 165

M2 77% 538.6 (M + 2H)²⁺ 166

M2 — — 167

M2 — 503.6 (M + 2H)²⁺ 168

M2 — 551.6 (M + 2H)²⁺ 169

M2 — 552.8 (M + 2H)²⁺ 170

M2 — 531.6 (M + 2H)²⁺ 171

M2 — 537.7 (M + 2H)²⁺ 172

M2 — 558.2 (M + 2H)²⁺ 173

M2 — 537.1 (M + 2H)²⁺ 174

M2 — 554.2 (M + 2H)²⁺ 175

M2 — 544.6 (M + 2H)²⁺ 176

M2 — 522.8 (M + 2H)²⁺ 177

M2 — 537.8 (M + 2H)²⁺ 178

M2 — 536.7 (M + 2H)²⁺ 179

M2 — 542.8 (M + 2H)²⁺ 180

M2 — 544.1 (M + 2H)²⁺ 181

M2 — 554.4 (M + 2H)²⁺ 182

M2 — 537.2 (M + 2H)²⁺ 183

M2 85% 515.1 (M + 2H)²⁺ 184

M2 47% 515.4 (M + 2H)²⁺ 185

M2 — 530.0 (M + 2H)²⁺ 186

M2 — 569.3 (M + 2H)²⁺ 187

M2 — 535.8 (M + 2H)²⁺ 188

M2 — 557.8 (M + 2H)²⁺ 189

M2 — 543.8 (M + 2H)²⁺ 190

M2 — 556.8 (M + 2H)²⁺ 191

M2 90% 1024.9 (M + H)⁺ 513.0 (M + 2H)²⁺ 192

M2 50% 525.1 (M + 2H)²⁺ 193

M2 34% 525.1 (M + 2H)²⁺ 194

M2 33% 525.1 (M + 2H)²⁺ 195

M2 56% 525.1 (M + 2H)²⁺ 196

M2 93% 1004.1 (M + H)⁺ 502.5 (M + 2H)²⁺ 197

M2 81% 521.6 (M + 2H)²⁺ 198

M2 75% 516.0 (M + 2H)²⁺

Where B is as Defined in Table 2

The compounds 101-148, 151-160, 162, 164, 165, 183, 184, and 191-198were produced from alkyne 3 using the corresponding azides 14 (B—N₃)using conditions closely analogous to those described below. The timerequired for each reaction to proceed to completion was variable and wasdependent upon several factors including: the specific substrates; theamount of Cu(I) salt used; the presence or absence of Hunig's base; andthe concentration of the reactants. Reactions were monitored for thedisappearance of the starting materials by TLC and/or LCMS and weretypically allowed to run for between about 2 h to about 72 b. Reactionswere stopped when analysis demonstrated that the starting alkynesubstrate had been substantially consumed. The workup and purificationprotocols are typical of those used previously. Slight modifications tothe described workup procedures may have been used (such modificationsinclude the use of different aqueous wash solutions, different organicsolvents for extraction, the use of other anhydrous salts for the dryingof organic extracts, and the employment of different solvent mixturesfor the chromatographic purification of the compounds). In all cases,the methods used for the workup of the reaction mixtures, the extractionof products, the drying of organic extracts, and for the isolation andpurification of the title compounds were typical of procedures familiarto those trained in the art of organic synthesis. There were no specificor unusual protocols employed in the isolation and purification of thereaction products that were found to be critical in these processes. Theisolated chemical yields for the synthesis of compounds 101-148,151-160, 162, 164, 165, 183, 184, and 191-198 were variable and areindicated in the penultimate column of Table 2.

Compounds 149, 171-182 and 185-190 were prepared from a cycloadditionreaction of azide compound 161 with the corresponding alkyne. Azidecompound 161 was prepared from amine 150, which in turn was preparedfrom the nitro compound 147. Compounds 169 and 170 were prepared from acycloaddition reaction of azide compound 167. Azide compound 167 wasprepared from amino compound 166, which in turn was prepared from thenitro compound 108.

The following Schemes demonstrate the general synthesis of compoundssuch as 149, 168, 171-182, and 185-190.

Synthesis of Compound 147

A solution of 1.550 g (1.97 mmol) of compound 1, 0.650 g (2.95 mmol) ofazide 1a, and 0.375 g (1.97 mmol) of CuI in 40 ml of THF (a few drops ofHunig's base in it) was stirred under argon for 6 h. To this reactionmixture was added 50 ml of 10% aqueous ammonia solution, and thesolution was allowed to stir for 10 min, then extracted with CH₂Cl₂(40×3), the combined CH₂Cl₂ layers were washed with brine, dried,concentrated, and purified through silica gel column chromatography togive 1.520 g of pure product 147.

Synthesis of Azide 1a

To a solution of 3.000 g (15.37 mmol) of compound 1b, 5.36 ml (30.73mmol) of Hunig's base in 30 ml of DMF at 0° C. was added 1.79 ml (23.05mmol) of MsCl. The reaction mixture was warmed up to 25° C. for 2 h. Tothe mixture was then added 1.998 g (30.73 mmol) of NaN₃, heated up to70° C. for 16 h. The reaction mixture was diluted with H₂O (50 ml),extracted with ether), the combined ether layers were washed with brine,dried, filtered, and concentrated to give 2.670 g of the desired product1a.

Synthesis of Compound 150

A solution of 0.570 g (0.57 mmol) of compound 147, 0.057 g of Pd/C (10%)in 10 ml of EtOH/EtOAc(1:1) was stirred under H₂ atmosphere (balloon)for 24 h. The reaction mixture was filtered through celite, washed withCH₂Cl₂, the filtrate was concentrated and dried to give the desiredproduct in quantitative yield MS: (M+2)/2 489.4.

Synthesis of Compound 161

To a solution of 0.101 g (1.55 mmol) of NaN₃ in 2 ml of H₂O and 2 ml ofCH₂Cl₂ at 0° C. was added 0.13 ml (0.78 mmol) of Tf₂O. The reactionmixture was stirred at 0° C. for 2 h, followed by extraction withCH₂C₂(3 ml×2). The combined CH₂Cl₂ layers were added to a solution of0.190 g (0.19 mmol) of compound 150, 0.11 ml of Et₃N in 2 ml of MeOH, 2ml of H₂O at 0° C. The new reaction mixture was warmed to 25° C. andstirred for 20 h. The reaction was diluted with saturated aqueous NaHCO₃(30 ml), extracted with CH₂Cl₂ (30 ml×3). The combined CH₂Cl₂ layerswere washed with brine, dried, filtered, concentrated, and purified togive 0.130 g of the product 161. MS: (M+2)/2 502.7.

Synthesis of the Following Compounds

Compounds 149, 168, 171-182, and 185 were made from azide 161 and thecorresponding alkyne shown in the Table 2A below.

TABLE 2A Compound Alkyne 149

168

171

172

173

174

175

176

177

178

179

180

181

182

185

186

187

188

189

190

The above compounds were made through the reaction Scheme shown below.The synthesis of compound 168 is given to demonstrate how the reactionwas generally performed.

A solution of 1.700 g (1.69 mmol) of compound 1, 0.333 g (3.39 mmol) ofpropargyl acetate, and 0.323 g (1.69 mmol) of CuI in 6.0 ml of THF (witha few drops of Hunig's base) was stirred under argon for 6 h. To theabove reaction mixture was added 50 ml of 10% aqueous ammonia solution,the solution was allowed to stir for 10 min, then, extracted with CH₂C₂(50 ml×3), the combined CH₂Cl₂ layers were washed with brine, dried,concentrated, and purified through silica gel column chromatography togive 1.900 g of pure product (168).

Synthesis of Compound 171 From 0.100 g of Compound 161: 0.060 g of 171.Synthesis of Compound 172 From 0.100 g of Compound 161: 0.081 g of 172.Synthesis of Compound 173 From 0.100 g of Compound 161: 0.066 g of 173.Synthesis of Compound 174 From 0.100 g of Compound 161: 0.072 g of 174.Synthesis of Compound 175 From 0.100 g of Compound 161: 0.072 g of 175.Synthesis of Compound 176 From 0.100 g of Compound 161: 0.088 g of 176.Synthesis of Compound 177 From 0.100 g of Compound 161: 0.073 g of 177.Synthesis of Compound 178 From 0.100 g of Compound 161: 0.065 g of 178.Synthesis of Compound 179 From 0.100 g of Compound 161: 0.072 g of 179.Synthesis of Compound 180 From 0.100 g of Compound 161: 0.072 g of 180.Synthesis of Compound 181 From 0.100 g of Compound 161: 0.038 g of 181.Synthesis of Compound 182 From 0.100 g of Compound 161: 0.038 g of 182.Synthesis of Compound 185 From 0.100 g of Compound 161: 0.042 g of 185.Synthesis of Compound 186 From 0.100 g of Compound 161: 0.082 g of 186.Synthesis of Compound 187 From 0.100 g of Compound 161: 0.085 g of 187.Synthesis of Compound 188 From 0.100 g of Compound 161: 0.082 g of 188.Synthesis of Compound 189 From 0.100 g of Compound 161: 0.040 g of 189.Synthesis of Compound 190 From 0.100 g of Compound 161: 0.040 g of 190.Synthesis of Compounds 166, 167, 169 and 170

Synthesis of Compound 9

A solution of 0.500 g (3.59 mmol) of compound 8, 0.600 g (4.31 mmol) ofthe bromide, and 1.490 g (10.78 mmol) of K₂CO₃ in 10 ml of DMF washeated at 70° C. for 16 h. The reaction mixture was diluted with H₂O (30ml), extracted with ether (50 ml×3), the combined ether layers werewashed with brine, dried, filtered and concentrated to give 0.720 g ofthe crude product. No further purification was done, directly used innext reaction.

Synthesis of Compound 10

To a solution of 0.720 g (3.65 mmol) of compound 9, 1.27 ml (7.31 mmol)of Hunig's base in 10 mil of DMP at 0° C. was added 0.43 ml (5.48 mmol)of MsCl. The reaction mixture was warmed up to 25° C. for 2 h. To themixture was added 0.475 g (7.31 mmol) of NaN₃. Subsequently, it washeated up to 70° C. for 16 h. The reaction mixture was diluted with H₂O(30 ml), extracted with ether, the combined ether layers were washedwith brine, dried, filtered, concentrated to give 0.680 g of the desiredproduct. It was pretty pure. No further purification was necessary.

Synthesis of Compound 108

A solution of 0.165 g (0.21 mmol) of compound 1, 0.070 g (0.32 mmol) ofazide 10, and 0.060 g (0.32 mmol) of CuI in 5 ml of THF (a few drops ofHunig's base in it) was stirred under argon for 4 h. To the abovereaction mixture was added 20 ml of 10% aqueous ammonia solution, andthe solution was allowed to stir for 10 min, extracted with CH₂Cl₂ (20ml×3), combined CH₂Cl₂ layers were washed with brine, dried,concentrated, and purified through preparative TLC to give 0.120 g ofthe product 108.

Synthesis of Compound 166

A solution of 0.120 g (0.57 mmol) of compound 108, 0.020 g of Pd/C (10%)in 8 ml of EtOH/EtOAc(1:1) was stirred under H₂ atmosphere (balloon) for24 h. The reaction mixture was the filtered through celite, washed withCH₂Cl₂, the filtrate was concentrated and dried to give 0.108 g of 166.

Synthesis of Compound 167

To a solution of 0.053 g (0.82 mmol) of NaN₃ in 2 ml of H₂O, 2 ml ofCH₂Cl₂ at 0° C. was added 0.07 ml (0.41 mmol) of Tf₂O. The reactionmixture was stirred at 0° C. for 2 h, extracted with CH₂Cl₂ (3 ml×2).The combined CH₂Cl₂ layers were added to a solution of 0.10 g (0.19mmol) of compound 166, 0.06 ml of Et₃N in 2 ml of MeOH and 2 ml of H₂Oat 0° C. The new reaction mixture was warmed to 25° C. and stirred for20 h. then diluted with saturated aqueous NaHCO₃ (30 ml), extracted withCH₂Cl₂ (30 ml×3). The combined CH₂Cl₂ layers were washed with brine,dried, filtered, concentrated, and purified to give 0.060 g of 167.

Synthesis of Compound 169

A solution of 0.055 g (0.055 mmol) of compound 167, 0.011 g (0.11 mmol)of propargyl acetate, and 0.010 g (0.055 mmol) of CuI in 1 ml of THF (afew drops of Hunig's base in it) was stirred under argon for 4 h. To theabove reaction mixture was added 20 ml of 10% aqueous ammonia solution,and the solution was allowed to stir for 10 min, extracted with CH₂Cl₂(20×3), combined CH₂Cl₂ layers were washed with brine, dried,concentrated, and purified through preparative TLC to give 0.038 g of169. MS: (M+2)/2 552.8.

Synthesis of Compound 170

A solution of 0.020 g (0.018 mmol) of compound 169, and 0.006 g (0.036mmol) of K₂CO₃ in 2 ml of MeOH was stirred at 25° C. for 4 h. Solventwas removed and the residue was dissolved in 2 ml of CH₂Cl₂. Thesuspension was filtered through pipette column, and filtrateconcentrated to give 0.016 g of 170. MS: (M+2)/2 531.6.

Example 2—Synthesis of Compounds 201-207 and 226

Schemes 103 and 104 below depict the synthesis of compounds 201-207 and226. See Table 3. Demethylation of clarithromyein yielded3′-N-desmethyl-clarithromycin 21. Amine 21 was selectively N-alkylatedwith tosylates 11 to produce alkyne 27. As shown in Scheme 104 alkyne 27is reacted with corresponding azides 14 in the presence of copper (I)iodide to selectively afford the triazoles 201-207 and 226.

Synthesis of 3′-N-Desmethyl-Clarithromycin 21

To a mixture of clarithromycin (1.00 g, 1.3 mmol) and NaOAc*3H₂0 (0.885g, 6.5 mmol) was added MeOH—H₂O (20 mL, 4:1), and the mixture heated to55-60° C. Iodine (0.330 g, 1.3 mmol) was added portion-wise and thereaction stirred at 55-60° C. for 3 h. The reaction mixture was pouredinto 50 mL CHCl₃ containing 1 mL ammonium hydroxide. It was extractedwith CHCl₃ (4×50 mL), washed with water (70 mL) containing 5 mL ammoniumhydroxide, dried (anhydrous Na₂SO₄), concentrated, and purified by flashchromatography (silica gel, CHCl₃:MeOH:NH₄OH 100:10:0.1) to afford 21.Yield: 0.9 g (92%).

Synthesis of Alkyne 27

A mixture of 3′-N-desmethyl-clarithromycin 21 and tosylate 11 inanhydrous THF and Hunig's base was stirred. The reaction was poured intoCH₂Cl₂, extracted with 2% aqueous NH₄OH and saturated brine. The organiclayer was dried over Na₂SO₄ and the solvent was evaporated away. Thecrude was purified on a silica gel column to give 27.

TABLE 3 Compound B Mac Yield LCMS 201

M3 89% 1008.9 (M + H)⁺ 202

M3 95% 1041.8 (M + H)⁺ 1063.7 (M + Na)⁺ 203

M3 89% 1006.9 (M + H)⁺ 1028.9 (M + Na)⁺ 204

M3 53% 1047.9 (M + H)⁺ 205

M3 39% 1047.9 (M + H)⁺ 206

M3 28% 1047.9 (M + H)⁺ 207

M3 43% 1047.9 (M + H)⁺ 226

M1 50% —

Example 3: Synthesis of Compounds 210-213

The macrolide oximes 210-213, see Table 4, were synthesized from alkynes400a to 400c by copper (I)-promoted cycloaddition with correspondingazides 14 in a manner analogous to the procedures presented previously.Alkyne precursors with substituted oxime functionality at the 9-positionof the macrocyclic ring were prepared from alkyne 27 and as shown below.

Synthesis of Alcohol 27a

To the alkyne 27 (0.700 g) was added 10 mL 0.9N HCl and the mixture wasstirred for 4 h at room temperature. The reaction mixture was saturatedwith sodium chloride and was adjusted to pH 8 using aqueous NH₄OHsolution. The solution was extracted with ethyl acetate (3×30 mL), dried(with Na₂SO₄), and concentrated under reduced pressure. Purification ofthe crude reaction mixture by flash chromatography (silica gel, 60%ethyl acetate in hexane) afforded 0.200 g (35% yield) of thedescladinose derivative 27. Data for 27; ¹HNMR (300 MHz, CDCl₃,partial): δ 0.82 (t, 3H), 2.25 (s, 3H), 3.00 (s, 3H), 3.25 (dd, 1H),3.55 (m, 2H), 3.70 (s, 1H), 3.85 (s, 1H), 3.95 (s, 1H), 4.40 (d, 1H),5.15 (dd, 1H).

Synthesis of Acetate 27b

To a solution of 27a (0.200 g. 0.32 mmol) in acetone (2 mL) was addedacetic anhydride (0.050 mL, 0.5 mmol) and the mixture was stirredovernight at room temperature. The reaction was quenched with water andextracted with ethyl acetate (3×50 ml). The combined organic fractionswere washed with saturated sodium bicarbonate (3×50 mL), dried(anhydrous Na₂SO₄), and concentrated under reduced pressure. The crudereaction mixture was purified by flash chromatography (silica gel, 50%ethyl acetate in hexane) to yield 0.100 g (50% yield) of acetate 27b.Data for 27b: ¹HNMR (300 MHz, CDCl₃, partial): δ 0.84 (t, 3H), 2.00 (s,3H), 2.20 (s, 3H), 2.90 (s, 3H), 3.00 (q, 1H), 3.25 (s, 1H, 3.47 (m,2H), 3.70 (bs, 1H), 3.82 (bs, 1H), 3.97 (s, 1H), 4.60 (d, 1H), 4.77 (dd,1H), 5.15 (dd, 1H).

Synthesis of Ketolide 27c

To a solution of acetate 27b (0.090 g, 0.134 mmol), EDC.HCl (0.172 g,0.90 mmol), and DMSO (0.171 mL, 2.41 mmol) in CH₂Cl₂ (1.5 mL) was addeddropwise a solution of pyridinium trifluoroacetate (0.174 g, 0.90 mmol)in CH₂Cl₂ (1 mL) at 15° C. The reaction mixture was slowly warmed up toroom temperature and stirred for 3 b. The reaction was quenched withwater (2 mL), and allowed to stir for 30 min. The mixture was thenpoured into CHCl₃ (50 mL), and the organic layer was washed with water(2×50 mL), dried (over anhydrous Na₂SO₄), and concentrated under reducedpressure. The crude material was purified by flash chromatography(silica gel, 30% ethyl acetate in hexane) to yield 0.070 g (78%) of theketolide 27c. Data for 27c: MS (ESI) m/e 668 (M+H)⁺; ¹HNMR (300 MHz,CDCl₃, partial): δ 0.86 (t, 3H), 2.00 (s, 3H), 2.24 (a. 3H), 2.70 (a.3H). 2.95-3.10 (m, 1H), 3.15-3.05 (m, 1H), 3.45-3.65 (m, 1H), 3.80 (q,1H), 3.90 (s, 1H), 4.28 (d, 1H), 4.40 (d, 1H), 4.76 (dd, 11H), 5.10 (dd,1H).

Synthesis of Oxime 400a

To a solution of 27c (2.0 g, 2.9 mmol) in MeOH (10 mL) was added(R)—N-Piperidin-3-yl-hydroxylamine hydrobromide (1.26 g. 4.4 mmol). Thereaction mixture was stirred at rt for 14 h. The mixture was then pouredinto (50 mL) and water (50 mL) the pH was adjusted to 11 by addition ofNH₄OH and the organic layer was separated and washed with brine (50 mL),dried (over anhydrous Na₂SO₄), and concentrated under reduced pressure.The crude material was purified by flash chromatography (silica gel,12:1 CH₂Cl₁ and 2M methanolic ammonia) to yield 2 g (78%) of the oxime400a as a 1:1 mixture of E/Z isomers. Data for 400a: MS (ESI) t/e 724.7(M+H)⁺.

Synthesis of Oxime 400b

Okime 400b was synthesized from alkyne 27c and(R)—N-Pyrollidin-3-yl-hydroxylamine hydrobromide using the conditionsdescribed above for the synthesis of oxime 400a. Data for 400b: MS (ESI)m/e 710.6 (M+H)⁺.

Synthesis of Oxime 400c

Oxime 400c was synthesized from alkyne 27c andN-[2-dimethtylaminoethyl]-hydroxylamine hydrobromide using theconditions described above for the synthesis of oxime 400a. Data for400bc: MS (ESI) m/e 726.5 (M+H)⁺.

Synthesis of Oxime Triazole 439

This triazole was synthesized from the alkyne 400a and the correspondingazide using the standard copper-promoted cycloaddition conditions aspreviously described.

Synthesis of Oxime Triazoles 444 and 445

These triazoles were synthesized from the alkyne 400b and thecorresponding azides 14 using the standard copper-promoted cycloadditionconditions as previously described.

Synthesis of Oxime Triazole 437

This triazole was synthesized from the alkyne 400c and the correspondingazide using the standard copper-promoted cycloaddition conditions aspreviously described.

TABLE 4 Compound B Mac Yield LCMS 210

M3A 76% 467 (M + 2H)²⁺ 933 (M + H)⁺ 211

M3B 62% 473 (M + 2H)²⁺ 945 (M + H)⁺ 212

M3C 27% 467 (M + 2H)²⁺ 213

M3C 37% 466 (M + 2H)²⁺ 930.8 (M + H)⁺

Example 4: Synthesis of Compounds 221-225

Compounds 221-225, see Table 5, were derived from a number of macrolidealkynes. A number of representative examples are shown below.

Synthesis of Compounds 222 and 223

Synthesis of Compound 92

To a solution of 1.00 g (1.30 mmol) of desmycocin in 10 ml of ethylalcohol was added 0.260 g (1.36 mmol) of p-toluenesulfonic acid atambient temperature. The reaction mixture was allowed to stir for 3 h,then diluted with 30 ml of saturated aqueous NaHCO₃, and extracted withEtOAc. The combined ethyl acetate extracts were washed with brine, driedover MgSO₄, and concentrated to give 1.220 g of 92 which was usedwithout further purification.

Synthesis of Compound 93

To a mixture of 0.250 g (0.29 mmol) of 92 and 0.486 g (5.92 mmol) ofNaOAc in 10 ml of MeOH/H₂O (80% MeOH) at 55° C. was added 0.075 g (0.29mmol) of solid iodine. The pH value of the reaction mixture wasmaintained at 9 by addition of 1 N NaOH at time intervals of 10, 30, and60 minutes after the addition of iodine. The reaction mixture wasstirred at 55° C. for 1 h following the last addition of NaOH solution,then diluted with 25 ml of saturated NaHCO₃ and extracted with EtOAc (50ml×2). The combined EtOAc extracts were washed sequentially with 15 mlof 5% NaS₂O₄ and brine, dried over MgSO₄, filtered and concentrated togive 0.221 g of 93.

Synthesis of Alkyne 94

A mixture of 0.200 g (0.24 mmol) of 93, 0.270 g (1.20 mmol) of tosylate11, 0.311 g (2.41 mmol) of di-isopropylethylamine and 10 mg ofdimethylaminopyridine in 5 ml of THF was allowed to stir at 55° C. for48 h. The mixture was diluted with 20 ml of saturated NaHCO₃, extractedwith EtOAc (30 ml×3). The combined organic layers were washed with brine(20 ml), dried over MgSO₄, filtered and concentrated to give 0.065 g ofdesired product 94 and 0.063 g of recovered starting material 93 afterpurification through flash column chromatography on silica gel.

Synthesis of Compound 222

A solution of 0.300 g (0.03 mmol) of alkyne 94, 0.018 g (0.06 mmol) ofazide 14ez and 0.006 g (0.03 mmol) of CuI in 3.0 ml of THF was degassed,then put under argon. To the mixture was added 4 drops of Hunig's base.The reaction was stirred at 25° C. for 6 h. To it was added 20 ml of 10%NH₄OH, stirred for 10 min, extracted with CHCl₂ (30 ml×3), combinedorganic layers were washed with brine, dried, concentrated, purifiedthrough preparative TLC to give 0.020 g of the final product.

Synthesis of Compound 223

A solution of 0.015 g (0.013 mmol) of compound 222 in 1.0 ml of 0.2 NHCl and 1.0 ml of acetonitrile was stirred at 25° C. for 4 h. To it wasadded 15 ml of saturated aqueous NaHCO₃ solution, the aqueous layer wasthen extracted with CH₂Cl_(a)(40 ml×3), combined organic layers werewashed with brine, dried, and concentrated to give 0.003 g of pure 223.

TABLE 5 Compound B Mac Yield LCMS 221

M4A 91% 927⁻ (M + H)⁺ 222

M5A 52% 1145.8 (M + H)⁺ 223

M5B 10% 1071.8 (M + H)⁺ 224

M6 70% 477.0 (M + 2H)²⁺ 225

M6 72% 460.0 (M + 2H)²⁺

Example 5: Synthesis of Azides 14

The azides 14 shown in Table 6 represent a sampling of the azides thatwere used to synthesize numerous compounds of the invention. The azideswere readily synthesized by methods known in the literature fromappropriate commercial starting materials.

TABLE 6 Azide Compound Structure 14gd

14ge

14gf

14gg

14gh

14fc

14gk

14gl

14fz

14ga

14gb

14fd

14fl

14bs

14ec

14ew

14ey

14fm

14fn

14dv

14ep

14et

14fq

14ft

14ez

14fp

Most of the azides compounds in Table 6 can be synthesized according toknown procedures with the specific route determined by the availablecommercial starting materials. When possible azides are produced fromthe corresponding substituted alkyl bromides by direct displacement withazide ion. When the required alkyl bromides are not readily available,the compounds are derived from substituted alkanols: to accomplish this,the alcohols are first activated as their sulfonyl ester derivatives andthen substituted with azide ion. If neither the required bromides noralkanols are commercially available, the azides are synthesized from thecorresponding carboxylic acids by reduction with borohydride to thecorresponding alcohols. The resulting alkanols are then treated as aboveto yield the azides. Finally, some azides of Table 6 are synthesizedfrom the corresponding substituted alkyl amines by reaction with triflicazide. In a few cases, azides are synthesized by modification of otherazides that are synthesized according to the methodologies above. Anexemplary synthesis of iodo azide 14zz is shown below in Scheme 175,which can further be functionalized with boronic acid derivatives to afurther variety of azide compounds.

Synthesis of Compound 98

A solution of 1.000 g (3.37 mmol) of benzyl bromide 97 and 0.930 g (6.74mmol) of K₂CO₃ in 20 ml of ethylene glycol was heated at 80° C. for 3 h.The reaction mixture was diluted with water (30 ml), then, extractedwith ethyl acetate (50 ml×3), combined ethyl acetate layers were washedwith brine (40 ml), dried (MgSO₄), filtered, concentrated, and purifiedto give 0.650 g of the desired product.

Synthesis of Compound 14zz

To a solution of 0.650 g (2.34 mmol) of compound 98, 0.81 ml (4.68 mmol)of Hunig's base in 10 ml of DMP at 0° C. was added 0.27 ml (3.51 mmol)of MsCl. The reaction mixture was subsequently warmed to ambienttemperature and stirred for 2 h. To the above reaction mixture was thenadded 0.304 g (4.68 mmol) of NaN₃. The new mixture was heated up to 70°C. for 24 h. The reaction mixture was diluted with water (50 ml),extracted with diethyl ether (40 ml×3), combined ether layers werewashed with water (15 ml×3), brine (30 ml), dried (MgSO₄), filtered andconcentrated to give 0.510 g of the desired product. This iodo compoundcan then be used for coupling with various boronic acids to obtain thedesired azide compound.

Example 6: Synthesis of Compounds 230-243

Compounds 230-243 were made using general procedures as described above.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention can be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1. A compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrugthereof, wherein T is a 14- or 15-membered macrolide connected via amacrocyclic ring carbon atom; R¹ and R³ independently are selected from:(a) H, (b) a C₁₋₆ alkyl group, (c) a C₂₋₆ alkenyl group, (d) a C₂₋₆alkynyl group, (e) —C(O)R⁵, (f) —C(O)OR⁵, (g) —C(O)—NR⁴R⁴, (h) —C(S)R⁵,(i) —C(S)OR⁵, (j) —C(O)SR⁵, or (k) —C(S)—NR⁴R⁴; R² is hydrogen or —OR¹²;A is selected from:—(a) a C₁₋₆ alkyl group, (b) a C₂₋₆ alkenyl group,(c) a C₂₋₆ alkynyl group, (d) a C₃₋₁₂ saturated, unsaturated, oraromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromnitrogen, oxygen, and sulfur, wherein i) 0-2 carbon atoms in any of(a)-(c) of A immediately above optionally is replaced by a moietyselected from 0, S(O)_(p), and NR⁵, and ii) each of the groups (a)-(e)immediately above optionally is substituted with one or more R⁵ groups;G is selected from: (a) —B′ and (b) —B′—Z—B″, wherein i) each B′ and B″is independently selected from (aa) an aryl group, (bb) a heteroarylgroup, (cc) a biaryl group, (dd) a fused bicyclic or tricyclicsaturated, unsaturated or aromatic ring system optionally containing oneor more heteroatoms selected from nitrogen, oxygen, and sulfur, (ee) a3-10 membered saturated or unsaturated heterocycle containing one ormore heteroatoms selected from nitrogen, oxygen, and sulfur, and (ff) a3-10 membered saturated, or unsaturated carbocycle, wherein each(aa)-(ff) optionally is substituted with one or more R¹¹ or R^(11a)groups; and ii) Z is selected from (aa) a single bond, (bb) a C₁₋₆ alkylgroup, (cc) a C₂₋₆ alkenyl group, (dd) a C₂₋₆ alkynyl group, (ee)—C(O)—, (ff) —C(O)O—, (gg) —C(O)NR⁴—, (hh) —C(═NR⁴)—, (ii) —C(═NR⁴)O—,(jj) —C(═NR⁴)NR⁴—, (kk) —S(O)_(p)—, (ll) —OC(O)—, (mm) —C(S)—, (nn)—C(S)NR⁴—, (oo) —C(NR⁴)S—, (pp) —C(O)S—, (qq) —O—, (rr) —NR⁴—, (ss)—NR⁴C(O)—, (tt) —OC(NR⁴)—, (uu) —NC(NR⁴)—, (vv) —C(S)O—, (ww) —SC(O)—,(xx) —OC(S)—, and (yy) —S(O)_(p)—; R⁴, at each occurrence, independentlyis selected from: (a) H, (b) a C₁₋₆ alkyl group, (c) a C₂₋₆ alkenylgroup, (d) a C₂₋₆ alkynyl group, (e) a C₆₋₁₀ saturated, unsaturated, oraromatic carbocycle, (f) a 3-12 membered saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromnitrogen, oxygen, and sulfur, (g) —C(O)—C₁₋₆ alkyl, (h) —C(O)—C₂₋₆alkenyl, (i) —C(O)—C₂₋₆ alkynyl, (j) —C(O)—C₆₋₁₀ saturated, unsaturated,or aromatic carbocycle, (k) —C(O)-3-12 membered saturated, unsaturated,or aromatic heterocycle containing one or more heteroatoms selected fromnitrogen, oxygen, and sulfur, (l) —C(O)O—C₁₋₆ alkyl, (m) —C(O)O—C₂₋₆alkenyl, (n) —C(O)O—C₂₋₆ alkynyl, (o) —C(O)O—C₆₋₁₀ saturated,unsaturated, or aromatic carbocycle, (p) —C(O)O-3-12 membered saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from nitrogen, oxygen, and sulfur, and (q) —C(O)NR⁶R⁶, whereinany of (b)-(p) optionally is substituted with one or more R⁵ groups,alternatively, NR⁶R⁶ forms a 3-7 membered saturated, unsaturated oraromatic ring including the nitrogen atom to which the R⁶ groups arebonded, wherein said ring is optionally substituted at a position otherthan the nitrogen atom to which the R⁶ groups are bonded, with one ormore moieties selected from O, S(O)_(p), N, and NR⁸; R⁵ is selectedfrom: (a) R⁷, (b) a C₁₋₈ alkyl group, (c) a C₂₋₈ alkenyl group, (d) aC₂₋₈ alkynyl group, (e) a C₃₋₁₂ saturated, unsaturated, or aromaticcarbocycle, (f) a 3-12 membered saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from nitrogen,oxygen, and sulfur, (g) two R⁵ groups, when present on the same carbonatom, can be taken together with the carbon atom to which they areattached to form a 3-7 membered carbocyclic ring or heterocyclic ringcontaining one or more heteroatoms selected from nitrogen, oxygen, andsulfur, (h) two R⁵ groups, when present on the same nitrogen atom, canbe taken together with the nitrogen atom to which they are attached toform a 3-7 membered heterocyclic ring optionally containing one or moreadditional heteroatoms selected from nitrogen, oxygen, and sulfur, (i)two R⁵ groups, when present on different carbon atoms, can be takentogether with the carbon atoms to which they are attached to form a 3-7membered carbocyclic ring or heterocyclic ring containing one or moreheteroatoms selected from nitrogen, oxygen, and sulfur, (j) two R⁵groups, when present on a carbon and a-nitrogen atom, can be takentogether with the carbon and nitrogen atoms to which they are attachedto form a 3-7 membered heterocyclic ring optionally containing one ormore additional heteroatoms selected from nitrogen, oxygen, and sulfur,and (k) two R⁵ groups, when present on different nitrogen atoms, can betaken together with the nitrogen atoms to which they are attached toform a 3-7 membered heterocyclic ring optionally containing one or moreadditional heteroatoms selected from nitrogen, oxygen, and sulfur;wherein any of (b)-(k) immediately above optionally is substituted withone or more R⁷ groups; R⁶, at each occurrence, independently is selectedfrom: (a) H, (b) a C₁₋₆ alkyl group, (c) a C₂₋₆ alkenyl group, (d) aC₂₋₆ alkynyl group, (e) a C₃₋₁₀ saturated, unsaturated, or aromaticcarbocycle, and (f) a 3-10 membered saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from nitrogen,oxygen, and sulfur, wherein any of (b)-(f) optionally is substitutedwith one or more moieties selected from: (aa) a carbonyl group, (bb) aformyl group, (cc) F, (dd) Cl, (ee) Br, (ff) I, (gg) CN, (hh) NO₂, (ii)—OR⁸, (jj) —S(O)_(p)R⁸, (kk) —C(O)R⁸, (ll) —C(O)OR⁸, (mm) —OC(O)R⁸, (nn)—C(O)NR⁸R⁸, (oo) —OC(O)NR⁸R⁸, (pp) —C(═NR⁸)R⁸, (qq) —C(R⁸)(R⁸)OR⁸, (rr)—C(R⁸)₂OC(O)R⁸, (ss) —C(R⁸)(OR⁸)(CH₂)_(r)NR⁸R⁸, (tt) —NR⁸R⁸, (uu)—NR⁸OR⁸, (v) —NR⁸C(O)R⁸, (ww) —NR⁸C(O)OR⁸, (xx) —NR⁸C(O)NR⁸R⁸, (yy)—NR⁸S(O)_(r)R⁸, (zz) —C(OR⁸)(OR⁸)R⁸, (ab) —C(R⁸)₂NR⁸R⁸, (ac) ═NR⁸, (ad)—C(S)NR⁸R⁸, (ae) —NR⁸C(S)R⁸, (af) —OC(S)NR⁸R⁸, (ag) —NR⁸C(S)OR⁸, (ah)—NR⁸C(S)NR⁸R⁸, (ai) —SC(O)R⁸, (aj) a C₁₋₈ alkyl group, (ak) a C₂₋₈alkenyl group, (al) a C₂₋₈ alkynyl group, (am) a C₁₋₈ alkoxy group, (an)a C₁₋₈ alkylthio group, (ao) a C₁₋₉ acyl group, (ap) —CF₃, (aq) —SCF₃—,(ar) a C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, and (as) a3-10 membered saturated, unsaturated, or aromatic heterocycle containingone or more heteroatoms selected from nitrogen, oxygen, and sulfur,alternatively, NR⁶R⁶ forms a 3-10 membered saturated, unsaturated oraromatic ring including the nitrogen atom to which the R⁶ groups areattached wherein said ring is optionally substituted at a position otherthan the nitrogen atom to which the R⁶ groups are bonded, with one ormore moieties selected from O, S(O)_(p), N, and NR⁸; alternatively,CR⁶R⁶ forms a carbonyl group; R⁷, at each occurrence, is selected from:(a) H, (b) ═O, (c) F, (d) Cl, (e) Br, (f) I, (g) —CF₃, (h) —CN, (i) —N₃,(j) —NO₂, (k) —NR⁶(CR⁶R⁶)_(t)R⁹, (l) —OR⁹, (m) —S(O)_(p)C(R⁶R⁶)_(t)R⁹,(n) —C(O)(CR⁶R⁶)_(t)R⁹, (o) —OC(O)(CR⁶R⁶)_(t)R⁹, (p)—SC(O)(CR⁶R⁶)_(t)R⁹, (q) —C(O)O(CR⁶R⁶)_(t)R⁹, (r) —NR⁶C(O)(CR⁶R⁶)_(t)R⁹,(s) —C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (t) —C(═NR⁶)(CR⁶R⁶)_(t)R⁹, (u)—C(═NNR⁶R⁶)(CR⁶R⁶)_(t)R⁹, (v) —C(═NNR⁶C(O)R⁶)(CR⁶R⁶)_(t)R⁹, (w)—C(═NOR⁹)(CR⁶R⁶)_(t)R⁹, (x) —NR⁶C(O)O(CR⁶R⁶)_(t)R⁹, (y)—OC(O)NR⁶(CR⁶R⁶)_(t)R⁹, (z) —NR⁶C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (aa)—NR⁶S(O)_(p)(CR⁶R⁶)_(t)R⁹, (bb) —S(O)pNR⁶(CR⁶R⁶)_(t)R⁹, (cc)—NR⁶S(O)pNR⁶(CR⁶R⁶)_(t)R⁹, (dd) —NR⁶R⁶, (ee) —NR⁶(CR⁶R⁶), (ff) —OH, (gg)—NR⁶R⁶, (hh) —OCH₃, (ii) —S(O)_(p)R⁶, (jj) —NC(O)R⁶, (kk) a C₁₋₆ alkylgroup, (ll) a C₂₋₆ alkenyl group, (mm) a C₂₋₆ alkynyl group, (nn) —C₃₋₁₀saturated, unsaturated, or aromatic carbocycle, and (oo) 3-10 memberedsaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of(kk)-(oo) optionally is substituted with one or more R⁹ groups;alternatively, two R⁷ groups can form —O(CH₂)_(u)O—; R⁸ is selectedfrom: (a) R⁵, (b) H, (c) a C₁₋₆ alkyl group, (d) a C₂₋₆ alkenyl group,(e) a C₂₋₆ alkynyl group, (f) a C₃₋₁₀ saturated, unsaturated, oraromatic carbocycle, (g) a 3-10 membered saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromnitrogen, oxygen, and sulfur, (h) —C(O)—C₁₋₆ alkyl, (i) —C(O)—C₁₋₆alkenyl, (j) —C(O)—C₁₋₆ alkynyl, (k) —C(O)—C₃₋₁₀ saturated, unsaturated,or aromatic carbocycle, and (l) —C(O)-3-10 membered saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from nitrogen, oxygen, and sulfur, wherein any of (c)-(k)optionally is substituted with one or more moieties selected from—: (aa)H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (ff) CN, (gg) NO₂, (hh) OH, (ii)NH₂, (jj) NH(C₁₋₆ alkyl), (kk) N(C₁₋₆ alkyl)₂, (ll) a C₁₋₆ alkoxy group,(mm) an aryl group, (nn) a substituted aryl group, (oo) a heteroarylgroup, (pp) a substituted heteroaryl group, and (qq) a C₁₋₆ alkyl groupoptionally substituted with one or more moieties selected from an arylgroup, a substituted aryl group, a heteroaryl group, a substitutedheteroaryl group, F, Cl, Br, I, CN, NO₂, CF₃, SCF₃, and OH; R⁹, at eachoccurrence, independently is selected from: (a) R¹⁰, (b) a C₁₋₆ alkylgroup, (c) a C₂₋₆ alkenyl group, (d) a C₂₋₆ alkynyl group, (e) a C₃₋₁₀saturated, unsaturated, or aromatic carbocycle, and (f) a 3-10 memberedsaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of(b)-(f) optionally is substituted with one or more R¹⁰ groups; R¹⁰, ateach occurrence, independently is selected from: (a) H, (b) ═O, (c) F,(d) Cl, (e) Br, (f) I, (g) —CF₃, (h) —CN, (i) —NO₂, (j) —NR⁶R⁶, (k)—OR⁶, (l) —S(O)pR⁶, (m) —C(O)R⁶, (n) —C(O)OR⁶, (o) —OC(O)R⁶, (p)NR⁶C(O)R⁶, (q) —C(O)NR⁶R⁶, (r) —C(═NR⁶)R⁶, (s) —NR⁶C(O)NR⁶R⁶, (t)—NR⁶S(O)pR⁶, (u) —S(O)pNR⁶R⁶, (v) —NR⁶S(O)pNR⁶R⁶, (w) a C₁₋₆ alkylgroup, (x) a C₂₋₆ alkenyl group, (y) a C₂₋₆ alkynyl group, (z) a C₃₋₁₀saturated, unsaturated, or aromatic carbocycle, and (aa) a 3-10 memberedsaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of(w)-(aa) optionally is substituted with one or more moieties selectedfrom R⁶, F, Cl, Br, I, CN, NO₂, —OR⁶, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)₂, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, and a C₁₋₆ acylgroup; R¹¹ and R^(11a) at each occurrence, independently is selectedfrom: (a) a carbonyl group, (b) a formyl group, (c) F, (d) Cl, (e) Br,(f) I, (g) CN, (h) NO₂, (i) OR⁸, (j) —S(O)_(p)R⁸, (k) —C(O)R⁸, (l)—C(O)OR⁸, (m) —OC(O)R⁸, (n) —C(O)NR⁸R⁸, (o) —OC(O)NR⁸R⁸, (p) —C(═NR⁸)R⁸,(q) —C(R⁸)(R⁸)OR⁸, (r) —C(R⁸)₂OC(O)R⁸, (s) —C(R)(OR⁸)(CH₂)_(r)NR⁸R⁸, (t)—NR⁸R⁸, (u) —NR⁸OR⁸, (v) —NR⁸C(O)R⁸, (w) —NR⁸C(O)OR⁸, (x) —NR⁸C(O)NR⁸R⁸,(y) —NR⁸S(O)pR⁸, (z) —C(OR⁸)(OR⁸)R⁸, (aa) —C(R⁸)₂NR⁸R⁸, (bb)═NR⁸, (cc)—C(S)NR⁸R⁸, (dd) —NR⁸C(S)R⁸, (ee) —OC(S)NR⁸R⁸, (ff) —NR⁸C(S)OR⁸, (gg)—NR⁸C(S)NR⁸R⁸, (hh) —SC(O)R⁸, (ii) —N₃, (jj) —Si(CH₃)₃, (kk)—O—Si(CH₃)₃, (ll) —Si(C₂H₅)₂CH₃, (mm) —O—Si(C₂H₅)₂CH₃, (nn) a C₁₋₈ alkylgroup, (oo) a C₂₋₈ alkenyl group, (pp) a C₂₋₈ alkynyl group, (qq) a C₁₋₉alkoxy group, (rr) a C₁₋₉ alkylthio group, (ss) a C₁₋₈ acyl group, (tt)a C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, and (uu) a 3-10membered saturated, unsaturated, or aromatic heterocycle containing oneor more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein(nn)-(pp) optionally are substituted with one or more R⁵ groups; R¹² isselected from: (a) H, (b) a C₁₋₆ alkyl group, (c) a C₂₋₆ alkenyl group,(d) a C₂₋₆ alkynyl group, (e) —C(O)R⁵, (f) —C(O)OR⁵, (g) —C(O)—NR⁴R⁴,(h) —C(S)R⁵, (i) —C(S)OR⁵, (j) —C(O)SR⁵, (k) —C(S)—NR⁴R⁴, (l) a C₃₋₁₀saturated, unsaturated, or aromatic carbocycle, (m) a 3-10 memberedsaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from nitrogen, oxygen, and sulfur, (n) a —(C₁₋₆alkyl) —C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, and (o) a—(C₁₋₆ alkyl)-3-10 membered saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from nitrogen,oxygen, and sulfur, wherein (a)-(d) and (l)-(o) optionally aresubstituted with one or more R⁵ groups; p at each occurrence is 0, 1, or2; r at each occurrence is 0, 1, or 2; and t at each occurrence is 0, 1,or
 2. 2. A pharmaceutical composition comprising a compound according toclaim 1, or a pharmaceutically acceptable salt, ester, N-oxide, orprodrug thereof and a pharmaceutically acceptable carrier.
 3. A methodfor treating or preventing a disease state in a mammal comprisingadministering to a mammal in need thereof an effective amount of acompound according to claim 1, or a pharmaceutically acceptable salt,ester, N-oxide, or prodrug thereof.
 4. A method of treating a microbialinfection in a mammal comprising administering to the mammal aneffective amount of a compound according to claim 1, or apharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. 5.A method according to claim 4 wherein said microbial infection is anuncomplicated skin or soft tissue infection (uSSTI).
 6. A methodaccording to claim 4 wherein said microbial infection is a communityacquired or community associated infection.
 7. A method according toclaim 6 wherein said microbial infection is an uncomplicated skin orsoft tissue infection (uSSTI).
 8. A method of treating a fungalinfection in a mammal comprising administering to the mammal aneffective amount of a compound according to claim 1, or apharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. 9.A method of treating a parasitic disease in a mammal comprisingadministering to the mammal an effective amount of a compound accordingto claim 1, or a pharmaceutically acceptable salt, ester, JV-oxide, orprodrug thereof.
 10. A method of treating a proliferative disease in amammal comprising administering to the mammal an effective amount of acompound according to claim 1, or a pharmaceutically acceptable salt,ester, N-oxide, or prodrug thereof.
 11. A method of treating a viralinfection in a mammal comprising administering to the mammal aneffective amount of a compound according to claim 1, or apharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.12. A method of treating an inflammatory disease in a mammal comprisingadministering to the mammal an effective amount of a compound accordingto claim 1, or a pharmaceutically acceptable salt, ester, N-oxide, orprodrug thereof.
 13. A method of treating a gastrointestinal motilitydisorder in a mammal comprising administering to the mammal an effectiveamount of a compound according to claim 1, or a pharmaceuticallyacceptable salt, ester, N-oxide, or prodrug thereof.
 14. A method oftreating or preventing a disease state in a mammal caused or mediated bya nonsense or missense mutation comprising administering to a mammal inneed thereof an effective amount of a compound according to claim 1, ora pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof,to suppress expression of the nonsense or missense mutation.
 15. Themethod according to claim 3, wherein the compound, or a pharmaceuticallyacceptable salt, ester, N-oxide, or prodrug thereof is administeredorally, parentally, or topically.
 16. A method of synthesizing acompound, or a pharmaceutically acceptable salt, ester, N-oxide, orprodrug thereof according to claim
 1. 17. A medical device containing acompound, or a pharmaceutically acceptable salt, ester, N-oxide, orprodrug thereof, according to claim
 1. 18. The medical device accordingto claim 17, wherein the device is a stent.